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Cited by 55Histone Deacetylase Inhibitors ResearchEpigenetics and DNA MethylationGenomics and Chromatin Dynamics

HDACs and the epigenetic plasticity of cancer cells: target the complexity

Open access
Brancolini, Claudio, Gagliano, Teresa, Minisini, Martina·2022·Pharmacology & Therapeutics
DOI 10.1016/j.pharmthera.2022.108190
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Abstract

Cancer cells must adapt to the hostile conditions of the microenvironment in terms of nutrition, space, and immune system attack. Mutations of DNA are the drivers of the tumorigenic process, but mutations must be able to hijack cellular functions to sustain the spread of mutant genomes. Transcriptional control is a key function in this context and is controlled by the rearrangement of the epigenome. Unlike genomic mutations, the epigenome of cancer cells can in principle be reversed. The discovery of the first epigenetic drugs triggered a contaminating enthusiasm. Unfortunately, the complexity of the epigenetic machinery has frustrated this enthusiasm. To develop efficient patient-oriented epigenetic therapies, we need to better understand the nature of this complexity. In this review, we will discuss recent advances in understanding the contribution of HDACs to the maintenance of the transformed state and the rational for their selective targeting.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that HDACs are critical but context-dependent regulators of cancer, with both pro-oncogenic and tumor-suppressive activities, so selective targeting requires understanding their multiprotein complexes. It surveys class I, IIa, and IV HDACs and their roles in therapy, resistance, and immunotherapy.

Key findings

  • As single agents, HDAC inhibitors are clinically limited to cutaneous T-cell lymphoma and peripheral T-cell lymphoma; all approved HDACIs are pan-selective inhibitors of zinc-dependent HDACs. A ClinicalTrials.gov snapshot reports 725 HDACI cancer trials: 351 completed, 137 terminated, 80 recruiting, 60 active not recruiting, 50 unknown, and 32 withdrawn; by phase, 424 phase 1, 387 phase 2, 30 phase 3, and 3 phase 4.
  • HDAC1/2, HDAC3, HDAC8, class IIa HDACs, and HDAC11 show context-dependent effects. For example, in GBM, HDAC1 silencing affects glioma stem cell proliferation, but in vivo absence of HDAC1 leads to a more aggressive/invasive phenotype via STAT3; high HDAC1 expression correlates with poorer prognosis, whereas HDAC2 expression correlates with better prognosis.
  • Immunotherapy combinations are highlighted: in the phase 2 PEMDAC trial, entinostat plus pembrolizumab in metastatic uveal melanoma achieved a median overall survival of 13.4 months versus a ten-month historical benchmark; in metastatic clear cell renal cell carcinoma, entinostat with high-dose IL2 downregulated Fox3p and reduced Tregs.
  • HDAC8 is frequently overexpressed in tumors; the HDAC8 inhibitor PCI-34051 decreases cell growth and causes apoptosis in T-cell-derived tumor lines, and HDAC8 deletion significantly reduces AML incidence while HDAC8 inhibition increases chemotherapy sensitivity in mice and patients.

Methods

  • Narrative review; no primary experimental data are reported. The paper focuses on zinc-dependent HDACs in classes I, IIa, and IV and their contribution to cancer and therapeutic targeting.
  • Data sources are published literature and clinical trial data obtained from ClinicalTrials.gov, including 725 clinical trials using HDACIs for cancer treatment.
  • Main analysis is a qualitative synthesis by HDAC class/isoform, covering structural features, multiprotein complexes, oncogenic and tumor-suppressive functions, DNA damage response, immunotherapy, resistance, and inhibitors.

Limitations

  • Stated by the authors: it remains unclear how HDACs select the right substrate in a time- and context-dependent manner; little is known about the multiprotein complexes that accompany different HDACs; and space limitations prevented citing all relevant manuscripts.
  • Stated by the authors: HDACs are frequently implicated in cancer but do not always involve epigenetic targets, and conflicting results exist about their biological functions.
  • Evident from the text: this is a narrative review without a systematic search or quantitative meta-analysis; many mechanistic claims derive from preclinical models, cell lines, or mouse studies, and the clinical trial data are descriptive registry counts rather than patient-level outcomes.

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Integrity signals

Registry

Crossref · 10.1016/j.pharmthera.2022.108190

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    The Sall4/Hdac2 complex represses melanoma-specific invasiveness genes through an epigenetic switch involving reduction of H3K27ac levels.

    “Here, the Sall4/Hdac2 complex represses their expression through an epigenetic switch involving the reduction of H3K27ac levels (Diener et al., 2021).”
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    HDAC1/2 deacetylate K518ac of GLI1 to allow its association with chromatin and activation of transcription.

    “HDAC1/2 deacetylate K518ac of GLI1 to allow its association with chromatin and activation of transcription (Canettieri et al., 2010).”
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    HDAC2, together with HDAC3, can form a noncanonical complex with PACS-1.

    “HDAC2, together with HDAC3, can form a noncanonical complex with PACS-1 (phosphofurin acidic cluster sorting protein-1).”
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    Lysine 85 of linker histone H1 is dynamically acetylated in response to DNA damage by the antagonistic activities of PCAF/KAT2B and HDAC1.

    “Lysine 85 of linker histone H1 is dynamically acetylated in response to DNA damage by the antagonistic activities of the acetyl-transferase p300/CBPassociated factor (PCAF/KAT2B) and HDAC1.”
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    HDAC2, but not HDAC1 and HDAC6, represses the formation of primary cilia in pancreatic ductal carcinoma cells.

    “For example, HDAC2, but not HDAC1 and HDAC6, represses the formation of primary cilia in pancreatic ductal carcinoma cells (Kobayashi et al., 2017).”
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    Findingcitation

    As of the data obtained from clinicaltrials.gov, 725 clinical trials for the use of HDACIs in cancer are listed, with 351 completed, 137 terminated, 80 recruiting, 60 active not recruiting, 50 unknown, and 32 withdrawn.

    “Status of 725 clinical trials for the use of HDACIs in Cancer Terminated (137) Active not recruiting (60) Recruiting (80) Completed (351) Unknown (50) Withdrawn (32) Phase 1 (424) Phase 2 (387) Phase 3 (30) Phase 4 (3)”
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    Premisecitation

    HDAC2 can affect the expression of a subset of genes regulated by EZH2/ARID1A, and SAHA/vorinostat can increase survival in mice with ARID1A-mutated cancer.

    “HDAC2 can affect the expression of a subset of genes regulated by EZH2/ARID1A, and SAHA/vorinostat can increase survival in mice with ARID1A-mutated cancer (Fukumoto et al., 2018).”
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    Premisecitation

    Acetylation at H1K85 promotes chromatin compaction through greater interaction with nuclear histones and recruitment of HP1, making cells more susceptible to death in response to genotoxic agents.

    “Acetylation at this residue promotes chromatin compaction through greater interaction with nuclear histones and recruitment of HP1 (heterochromatin protein 1).A condition that makes cells more susceptible to death in response to genotoxic agents, possibly due to an increased amount of DNA damage (Li et al., 2018).”
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    Premisecitation

    The deacetylase activities of HDAC1/2 act as limiting factors to concentrate classical NHEJ complexes at the cleaved site by preventing their spread along the chromosome.

    “Here, it was proposed that the deacetylase activities of HDAC1/2 act as limiting factors to concentrate the classical NHEJ complexes at the cleaved site by preventing their spread along the chromosome (Rother et al., 2020).”
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    Interpretationnone given

    HDACs are promising targets for cancer therapy because their activities need to be hijacked to maintain the transformation state and they are directly responsible for transformation events.

    “There are two main reasons that make HDACs promising targets for cancer therapy: i) their activities need to be hijacked to maintain the transformation state; ii) they are directly responsible for transformation events.”
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    • Rests on an assumption: HDAC activities need to be hijacked to maintain the transformation state.
    • Rests on an assumption: HDACs are directly responsible for transformation events.

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    Premisecitation

    In colon cancer, miR-500a-5p targeting the 3' end of HDAC2 mRNA is downregulated during cancer progression and HDAC2 is necessary to maintain proliferation and invasion of neoplastic cells.

    “Similarly, in colon cancer, miR-500a-5p targeting the 3' end of HDAC2 mRNA is downregulated during cancer progression and HDAC2 is necessary to maintain proliferation and invasion of neoplastic cells (Tang et al., 2019).”
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    Premisecitation

    Knockdown of HDAC1/2 is sufficient to increase acetylation of H3K9/14 at the SOX11 promoter and increase its expression.

    “Although there are several aspects of this mechanism that deserve further validation, knockdown of HDAC1/2 is sufficient to increase acetylation of H3K9/14 at the SOX11 promoter and increase its expression.(Mohanty et al., 2019).”
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    Although Sall4 is required for primary tumor growth, loss of Sall4 results in increased metastatic burden.

    “Although Sall4 is required for primary tumor growth, loss of Sall4 results in increased metastatic burden.”
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    The catalytic activity of HDAC1 is modulated by serine phosphorylation and cancer cells can sustain it.

    “The catalytic activity of HDAC1 is modulated by serine phosphorylation (Pflum, Tong, Lane, & Schreiber, 2001) and cancer cells can sustain it (Citro, Miccolo, Meloni, & Chiocca, 2015).”
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    Premisecitation

    The CoREST complex, via LSD1/KDM1A, catalyzes demethylation of mono- and dimethylated lysine 4 of histone H3, while via HDAC1/2 it can deacetylate H3K27ac.

    “Via LSD1/KDM1A (lysine-specific demethylase 1), it catalyzes the demethylation of mono-and dimethylated lysine 4 of histone H3, while via HDAC1/2 it can deacetylate H3K27ac (Shi et al., 2004).”
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    Premisecitation

    PACS-1 maintains genome stability by buffering replication stress and protects HDAC2 and HDAC3 from degradation in replication forks.

    “During the cell cycle, PACS-1 can accumulate in the nucleus, where it maintains genome stability by buffering replication stress.The action of PACS-1 is important in protecting HDAC2 and HDAC3 from degradation in replication forks and thus can support the establishment of the desired chromatin microenvironment (Mani et al., 2020).”
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    Premisecitation

    Loss of ARID1A is associated with a lack of recruitment of HDAC1 and an increase in histone H4 acetylation in regulated genomic regions.

    “Finally, loss of ARID1A is associated with a lack of recruitment of HDAC1 and an increase in histone H4 acetylation in regulated genomic regions (Nagarajan et al., 2020).”
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    Premisecitation

    The SIN3A-HDAC1/2 complex silences BMP6 expression and promotes metastatic spread and tumor growth by suppressing BMP6-activated SMAD5 signaling in melanoma.

    “Here, the SIN3A-HDAC1/2 complex silences BMP6 expression and promotes metastatic spread and tumor growth by suppressing BMP6-activated SMAD5 signaling (Min et al., 2020).”
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    Premisecitation

    Tyr72 plays an important role in regulating HDAC1 stability, and can be phosphorylated by EGFR; this phosphorylation impinges the anti-apoptotic role of HDAC1 and the repression of BIM1.

    “In particular, Tyr72 plays an important role in regulating HDAC1 stability, and can be phosphorylated by EGFR.This phosphorylation impinges the anti-apoptotic role of HDAC1 and the repression of the proapoptotic BH3-only family member BIM1 (Bahl et al., 2021).”
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    Premisecitation

    Direct dysfunction of HDAC1/2 is frequently observed in the form of expression levels in various tumors, whereas mutations are rare.

    “Direct dysfunction of these HDACs is frequently observed in the form of expression levels in various tumors, whereas mutations are rare (http:// www.cbioportal.org).”
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    Premisecitation

    HDAC1 interacts with ARID1A and tamoxifen may promote recruitment of HDAC1 to ER complexes to mediate a repressive effect.

    “HDAC1 interacts with ARID1A and tamoxifen may promote recruitment of HDAC1 to ER complexes to mediate a repressive effect (Papachristou et al., 2018).”
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    Premisecitation

    Sall4 is strongly upregulated in hyperplastic, melanoma-prone murine melanocytes, where it sustains cell proliferation.

    “The TF Sall4, also known as stem cell factor (Zhan et al., 2006), is strongly upregulated in hyperplastic, melanoma-prone murine melanocytes, where it sustains cell proliferation (Diener et al., 2021).”
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    Premisecitation

    HDAC1/2 are highly homologous (>80% aa identity), often fully interchangeable, and are recruited to various multiprotein complexes involved in epigenetic control of gene expression.

    “These two HDACs are highly homologous (> 80% aa identity), often fully interchangeable, and are recruited to various multiprotein complexes involved in epigenetic control of gene expression (Millard et al., 2017).”
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    Premisecitation

    Inactivating mutations in ARID1A have been reported in treatment-resistant tumours and metastases as well as in ER+ breast cancer.

    “Recently, inactivating mutations in this gene have been reported in treatment-resistant tumours and metastases (Yates et al., 2017) as well as in ER+ breast cancer (Pereira et al., 2016).”
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    Premisecitation

    In the PEMDAC trial, median overall survival was 13.4 months, longer than the 10-month historical benchmark.

    “The median overall survival of 13.4 months achieved was longer than the ten-month benchmark survival determined from historical data (Ny et al., 2021).”
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    Interpretationreasoning

    Cancer cells utilize class I HDACs to create an immune-repressive environment and orchestrate immune cell activities.

    “Collectively, these observations suggest that cancer cells utilize class I HDACs to create an immune-repressive environment and orchestrate immune cells activities.”
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    Premisecitation

    HDAC2 is modulated by CSF1 signaling and suppresses granulocytic chemokine expression in carcinoma-associated fibroblasts, limiting MDSC infiltration.

    “HDAC2 is modulated by CSF1 signaling and suppresses granulocytic chemokine expression in carcinoma-associated fibroblasts, limiting MDSC infiltration.”
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    Premisecitation

    In patients with metastatic clear cell renal cell carcinoma, entinostat in combination with high dose of IL2 led to downregulation of Fox3p expression and a reduction in the number of Tregs, enhancing anti-tumor immunity.

    “In patients with metastatic clear cell renal cell carcinoma, entinostat in combination with high dose of IL2 led to downregulation of Fox3p expression and a reduction in the number of Tregs.An effect that enhanced anti-tumor immunity and showed promising clinical activity (Pili et al., 2017).”
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    Premisecitation

    Benzamides and in particular MS-275/entinostat is considered a specific class I inhibitor and shows some selectivity for HDAC1/2/3 over HDAC8.

    “Benzamides and in particular MS-275/ entinostat (Fig. 3) is considered a specific class I inhibitor and shows some selectivity for HDAC1/2/3 over HDAC8 (Hu et al., 2003).”
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    Premisecitation

    NCOR1 and SMRT/NCOR2 are fundamental for stabilization of HDAC3 and maturation of catalytic activity.

    “These partners are fundamental for the stabilization of HDAC3 and the maturation of catalytic activity (Emmett & Lazar, 2019).”
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    After screening 107 compounds, entinostat was isolated because it abrogated tumor growth after perturbing the transcriptome in GEP-NET.

    “After screening with 107 different compounds, entinostat was isolated because it abrogated tumor growth, after perturbing the transcriptome in GEP-NET (Alvarez et al., 2018).”
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    Premisecitation

    This switch results in an epigenetic reset that impairs plasma cell differentiation and impinges an immature memory B cell fate.

    “This switch in partner binding results in an epigenetic reset that impairs the plasma cell differentiation program and instead impinges an immature memory B cell fate.”
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    Premisecitation

    KO of HDAC1 and/or HDAC2 in mouse ES cells results in lagging chromosomes at the anaphase, micronuclei formation, and monopolar spindles.

    “Accordingly, the KO of HDAC1 and/or HDAC2 in mouse ES cells results in lagging chromosomes at the anaphase, micronuclei formation, and monopolar spindles (Jamaladdin et al., 2014).”
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    Premisecitation

    A reprogramming activity towards an immune-permissive tumor microenvironment was confirmed in another study, with beneficial therapeutic effects.

    “A reprogramming activity towards an immunepermissive tumor microenvironment was confirmed in another study, with beneficial therapeutic effects (Hicks et al., 2021).”
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    Premisecitation

    Entinostat potentiates immunotherapy elicited by an anticancer vaccine designed on human carcinoembryonic antigen, with increased inflammation, enhanced infiltration of activated CD8+ T cells, increased IFNγ and decreased regulatory T-cells.

    “Entinostat also potentiates immunotherapy elicited by an anticancer vaccine designed on human carcinoembryonic antigen.In the presence of entinostat, the tumor microenvironment is marked by increased inflammation, enhanced infiltration of activated CD8+ T cells with maximal granzyme B, T-cell responses to different tumorassociated antigens, increased IFNγ and decreased of regulatory T-cells (Hicks”
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    Premisecitation

    TBL1X and TBL1XR1 contain WD repeats involved in histone recognition and interaction with the ubiquitylation machinery.

    “These two proteins contain WD repeats involved in histone recognition and interaction with the ubiquitylation machinery (Yoon et al., 2003).”
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    Premisecitation

    HDAC3 provides H3K27 deacetylase activity at the RUNX2 promoter, recruited by binding with CBX4.

    “HDAC3 provides H3K27 deacetylase activity at the RUNX2 promoter, where it is recruited by binding with CBX4 (Wang et al., 2016).”
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    Interpretationcitation

    HDAC3 can control DNMT1 levels directly by deacetylating it and indirectly by stabilizing MYC.

    “Therefore, HDAC3 can control DNMT1 levels in two different ways: i) directly by deacetylating it and ii) indirectly by stabilizing MYC.”
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    DNMT1 transcription is stimulated by MYC, whose stability is reduced after inhibition by HDAC3.

    “In addition, DNMT1 transcription is stimulated by MYC, whose stability is reduced after inhibition by HDAC3.”
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    Premisecitation

    Some catalytically independent activities of Hdac3 were observed in liver, a feature common to class IIa HDACs.

    “Interestingly, some catalytically independent activities of Hdac3 were observed in liver, a feature common to class IIa HDACs (Sun et al., 2013).”
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    Premisecitation

    HDAC3 promotes deacetylation of FoxO3 and downregulation of Dicer, aiding metastatic potential.

    “HDAC3, which promotes deacetylation of FoxO3 and downregulation of Dicer, aids metastatic potential (Zhang et al., 2017).”
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    Premisecitation

    In liver, Hdac3 exerts non-redundant deacetylase activity against H3K9ac, accompanied by increase in H3K9me3.

    “In the liver Hdac3 exerts a non-redundant deacetylase activity against H3K9ac, which is accompanied by an increase in H3K9me3 (Ji et al., 2019).”
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    Premisecitation

    PD-1 is generally expressed on tumor-infiltrating T cells, while PD-L1 is often highly expressed on tumor to inhibit T cell activation and cytotoxicity.

    “PD-1 is generally expressed on tumor-infiltrating T cells, while its ligand (PD-L1) is often highly expressed on tumor to inhibit tumor-infiltrating T cell activation and cytotoxicity.(Constantinidou, Alifieris, & Trafalis, 2019).”
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    Premisecitation

    This genomic instability activates oncogenic signalling, impairs p53, leading to early onset spontaneous hepatocellular carcinoma in Hdac3-/- mice.

    “This genomic instability activates oncogenic signalling pathways and impairs p53 activities, leading to early onset of spontaneous hepatocellular carcinoma in Hdac3 -/-mice.(Bhaskara et al., 2010).”
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    Premisecitation

    HDAC3 controls interferon response and antigen presentation gene expression, restoring immune surveillance.

    “HDAC3 is not only involved in the repression of CREBBPtarget genes, but also controls the interferon response and expression of antigen presentation genes, thus restoring the immune surveillance.”
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    Premisecitation

    SPOP is the most frequently mutated gene in human primary prostate cancer.

    “The Speckle-type POZ protein (SPOP), the substrate-binding adaptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, is the most frequently mutated gene in human primary prostate cancer.”
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    Premisecitation

    Efficiency of HR and NHEJ repair pathways is reduced in absence of Hdac3, and chromosome breaks/gaps in mitosis increase.

    “The efficiency of both HR and NHEJ repair pathways is reduced in the absence of Hdac3, and in these null cells the number of chromosome breaks and gaps observed in mitosis is increased.”
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    Premisecitation

    RGFP966 impairs growth of B-cell lymphomas in which PD-L1 was deleted, but not WT cells.

    “Importantly, the HDAC3-specific inhibitor RGFP966 (Fig. 3) impairs the growth of B-cell lymphomas in which PD-L1 was deleted, but not that of WT cells.”
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    Premisecitation

    Regulation of H3K9ac/H3K9me3 turnover is one of first steps in DSB repair and allows binding of HAT Tip60 to DSB foci.

    “Regulation of H3K9ac/H3K9me3 turnover is one of the first steps in the DSB repair pathway and allows binding of HAT Tip60 to DSB foci.”
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    Premisecitation

    HDAC3 interacts with AKT at the plasma membrane and facilitates polyubiquitylation of the lysine-63-chain and phosphorylation of AKT by deacetylation.

    “Mechanistically, HDAC3 interacts with AKT at the plasma membrane and facilitates polyubiquitylation of the lysine-63-chain and phosphorylation of AKT, by deacetylation.”
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    Premisecitation

    This dual epigenetic targeting may influence additional antiproliferative mechanisms and enhance antitumor immune surveillance.

    “Certainly, this dual epigenetic targeting may influence additional antiproliferative mechanisms and further enhance antitumor surveillance by the immune system (Chiappinelli et al., 2015).”
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    Premisecitation

    HDAC3, like HDAC1/2, can control this acetylation, and its depletion impairs DNA repair, leading to CPD accumulation.

    “HDAC3, like HDAC1/2, can control this acetylation, and its depletion impairs DNA repair, leading to CDP accumulation.”
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    Premisecitation

    HDAC3 inhibition restores tumor-infiltrating lymphocyte killing of DLBCL cells in an MHC class I and II dependent manner and synergizes with PD-L1 blocking antibodies.

    “Practically, HDAC3 inhibition is sufficient to restore the capacity of tumor-infiltrating lymphocytes to kill DLBCL cells in a major histocompatibility complex (MHC) class I and II dependent manner, and to synergize with PD-L1 blocking antibodies (Mondello et al., 2020).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HDAC8 catalyzes deacetylation of histone substrates H3/H4 with efficiency influenced by distal protein-protein interactions or acetyllysine chain accessibility.

    “HDAC8 catalyzes the deacetylation of histone substrates (H3/H4) with an efficiency that can be influenced by distal protein-protein interactions or by acetyllysine chain accessibility (Castañeda et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Castañeda et al., 2017

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cohesin complex is important for spatial organization of genome, chromosome segregation, and genome-related functions from gene expression to DNA repair.

    “This complex is important for the spatial organization of the genome and the segregation of chromosomes and influences several genome-related functions, from gene expression to DNA repair (Broughm et al., 2012;Haarhuis, Elbatsh, & Rowland, 2014;Singh, McKinney and Gerton, 2020;Lee, Sengupta, Villagra, Rezai-Zadeh and Seto, 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Broughm et al., 2012

      Not checked in the free run.

    • cites Haarhuis et al., 2014 source

      Not checked in the free run.

    • cites Singh et al., 2020

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CdLS patients have congenital anomalies including distinctive facial features, upper limb abnormalities, intellectual disability, and other symptoms.

    “Patients suffering for this genetic disorder are characterized by congenital anomalies which consist of distinctive facial features, upper limb abnormalities, intellectual disability, and other symptoms (Dowsett et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dowsett et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HDACIs can repress binding between HDAC8 and YY1, restoring YY1 acetylation that suppresses mutant TP53 transcription in triple negative breast cancer.

    “HDACIs can repress the binding between HDAC8 and Yin Yang 1 (YY1), restoring the acetylation of YY1 TF that causes the suppression of mutant TP53 transcription in triple negative breast cancer (Wang et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blockade of HDAC8 by PCI-34051 decreases cell growth and causes apoptosis in T-cell derived tumor lines.

    “Accordingly, the blockade of HDAC8 by a specific inhibitor, (PCI-34051, Fig. 3), decreases cell growth and causes apoptosis in T-cell derived tumor lines (Balasubramanian et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Balasubramanian et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In neuroblastoma, HDAC8 correlates with poor overall survival, and its knockout leads to increased cell differentiation and cell cycle arrest.

    “In neuroblastoma, HDAC8 correlates with poor overall survival, and its knockout leads to increased cell differentiation and cell cycle arrest (Oehme et al. , 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Oehme et al., 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HDAC8 gene is on the X chromosome near the X inactivation center and encodes a 377 amino acid protein.

    “The HDAC8 gene is located on the X chromosome, near the X inactivation center, and encodes a 377 amino acid long protein (Hu et al., 2000;Lee, Sengupta, Villagra, Rezai-Zadeh, & Seto, 2006;Somoza et al., 2004;Van den Wyngaert et al., 2000).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hu et al., 2000

      Not checked in the free run.

    • cites Lee et al., 2006

      Not checked in the free run.

    • cites Somoza et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Missense mutations in HDAC8 are responsible for Cornelia de Lange Syndrome and associated spectrum disorders.

    “Missense mutations in HDAC8 are responsible for Cornelia de Lange Syndrome (CdLS) and associated spectrum disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dowsett et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of HDAC8 reduces incidence of AML and HDAC8 inhibitor increases sensitivity of AML cells to chemotherapy in mice and patients.

    “Importantly, deletion of HDAC8 significantly reduces the incidence of AML and treatment with a HDAC8 inhibitor increases the sensitivity of AML cells to chemotherapy in both mice and patients.(Qi et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Qi et al., 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HDAC8 protein is primarily nuclear, acts as a transcriptional repressor, and shows ubiquitous expression.

    “The HDAC8 protein is localized primarily in the nucleus, where it acts as a transcriptional repressor and shows a rather ubiquitous expression (Buggy et al., 2000;Hu et al., 2000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Buggy et al., 2000 source

      Not checked in the free run.

    • cites Hu et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hdac8 interacts with Tp53 and Hdac8-deficient LT-HSCs exhibit hyperacetylation and activation of TP53, causing increased apoptosis under stress.

    “Here, Hdac8 interacts with Tp53 and Hdac8-deficient LT-HSCs exhibit hyperacetylation and activation of TP53, causing increased apoptosis under various stress conditions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hua et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BRAF/MEK inhibitors plus entinostat synergize to induce DNA damage and suppress DDR genes involved in HR and NHEJ.

    “Interestingly, BRAF/MEK inhibitors in combination with entinostat (a preferred HDAC1/2/3 inhibitor) synergize to induce DNA damage and suppress expression of DDR genes involved in both HR and NHEJ (Maertens et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Maertens et al., 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CdLS is also caused by mutations in SMC1A, SMC3, RAD21, or NIBPL.

    “In addition to dysfunctions in HDAC8, CdLS is caused by mutations in genes encoding the cohesion structural proteins SMC1A, SMC3 and RAD21 or the cohesin assembly factor NIBPL (Avagliano et al., 2020;Watrin, Kaiser, & Wendt, 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Avagliano et al., 2020

      Not checked in the free run.

    • cites Watrin et al., 2016

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Somatic mutations of cohesin subunits are present in a variety of human cancers.

    “Another element of variability that should be considered is the presence of somatic mutations of the cohesin subunits in a variety of human cancers (Hill, Kim, & Waldman, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hill et al., 2016

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HDAC8 has a shorter carboxy-terminal tail, phosphorylated by PKA, and can utilize Zn2+ or Fe2+ for catalysis.

    “HDAC8 has the shorter carboxy-terminal tail, which is phosphorylated by PKA and can utilize either Zn 2+ or Fe 2+ for catalysis (Gantt, Gattis, & Fierke, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gantt et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HDAC8 inhibition suppresses cancer metastasis and chemotherapy resistance.

    “In this scenario HDAC8 is an important player since its inhibition suppresses cancer metastasis and chemotherapy resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tang et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Simultaneous treatment with both inhibitors increases TP53 acetylation and activity.

    “On the other hand, simultaneous treatment with both inhibitors increases TP53 acetylation and activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Long et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Silencing of HDAC4 upregulates BIM and inactivates mTORC1, leading to altered autophagy flux and cell death.

    “Conversely, silencing of HDAC4 leads to upregulation of the pro-apoptotic BH3-only protein BCL2L11/BIM and causes inactivation of mTORC1, two actions that lead to alterations in autophagy flux and cell death (Wu et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wu et al., 2020

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An epigenetic regulation previously observed for other class IIa is possibly mediated by MEF2 TFs.

    “An epigenetic regulation previously observed for others class IIa and possibly mediated by MEF2 TFs (Clocchiatti et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Clocchiatti et al., 2015

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Class IIa HDACs cannot be unambiguously classified as tumor suppressors or oncogenes, and their contribution to cancer varies by context.

    “Although several studies have reported a role of class IIa HDACs in cancer, they cannot be unambiguously classified as tumor suppressors or oncogenes, and their contribution to cancer development might vary from context to context.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HDAC8 binds SMAD3/4 complex and creates a repressive environment at SIRT7 promoter.

    “HDAC8 can bind the SMAD3/4 complex and supplies its epigenetic influence, by creating a repressive environment at the SIRT7 promoter.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tang et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NAC1 can bind HDAC4 and impedes phosphorylation of deacetylase, which prevents nuclear export and causes nuclear accumulation.

    “NAC1 can bind HDAC4 and impedes phosphorylation of deacetylase, which prevents nuclear export and causes nuclear accumulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhang et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anti-BRAF/MEK therapy promotes HDAC8 expression, which suppresses BIM and causes resistance in melanoma cell lines.

    “The anti-BRAF/MEK therapy can promote expression of HDAC8, which in turn suppresses expression of the pro-apoptotic gene BIM and causes resistance in melanoma cell lines.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Emmons et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HDAC8-TP53 interaction increases after quizartinib and leads to TP53 inactivation, allowing leukemia cell survival.

    “Indeed, their interaction increases after treatment with quizartinib and leads to inactivation of TP53, which allows leukemia cell survival.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Long et al., 2020

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Class IIa HDACs may act as readers of acetylated lysine, directing other HDAC subtypes to complete deacetylation.

    “It has been suggested that class IIa HDACs may act as readers of acetylated lysine, directing other HDAC subtypes (Fig. 4) to complete the deacetylation steps (Brancolini, Di Giorgio, Formisano, & Gagliano, 2021;Di Giorgio & Brancolini, 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Brancolini et al., 2021

      Not checked in the free run.

    • cites Di Giorgio & Brancolini, 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SENEBLOC controls HDAC5 levels, which affect H3K9 and H4K5 acetylation levels at the proximal promoter of CDKN1A.

    “This effect is achieved by two distinct strategies: i) by favouring MDM2-TP53 interaction, which reduces transcriptional output at the CDKN1A promoter, ii) by controlling HDAC5 levels, which affect H3K9 and H4K5 acetylation levels at the proximal promoter of CDKN1A (Xu et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xu et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SENEBLOC favours MDM2-TP53 interaction, which reduces transcriptional output at the CDKN1A promoter.

    “This effect is achieved by two distinct strategies: i) by favouring MDM2-TP53 interaction, which reduces transcriptional output at the CDKN1A promoter, ii) by controlling HDAC5 levels, which affect H3K9 and H4K5 acetylation levels at the proximal promoter of CDKN1A (Xu et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Xu et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HDAC8 regulates multiple signaling pathways, with MAPK important for resistance.

    “Mass spectrometry-based phosphoproteomic analysis revealed that HDAC8 regulates multiple signaling pathways, of which the MAPK pathway is important for resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Emmons et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In breast cancer cells, SerRS acetylation and nuclear translocation are strongly inhibited.

    “In contrast, in breast cancer cells, SerRS acetylation and nuclear translocation are strongly inhibited.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhao et al., 2021

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Silencing of HDAC11 blocks the cell cycle (mainly in G2/M phase) and induces abnormal mitotic spindle formation and cell death.

    “Functional studies have shown that silencing of HDAC11 blocks the cell cycle (mainly in G2/M phase) and induces abnormal mitotic spindle formation and cell death.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Thole et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacological inhibition of TGF-β can restore TCA cycle enzymes expression and reduce tumour growth in vivo.

    “Moreover, pharmacological inhibition of TGF-β can restore TCA cycle enzymes expression and reduce tumour growth in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nam et al., 2021

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In renal clear cell carcinoma, loss of TCA cycle enzymes expression marks the metastatic tissues and is a peculiar feature of this type of tumour.

    “In renal clear cell carcinoma loss of TCA cycle enzymes expression marks the metastatic tissues and is a peculiar feature of this type of tumour.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nam et al., 2021

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This reduction correlates with and depends on the downregulation of the co-activator PGC-1α.

    “This reduction correlates with and depends on the downregulation of the co-activator PGC-1α.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nam et al., 2021

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When glucose and glutamine supply is disrupted in HDAC5-inhibited cancer cells, apoptotic cell death significantly increases and tumour growth is reduced in vivo.

    “However, when glucose and glutamine supply is disrupted in HDAC5inhibited cancer cells, apoptotic cell death significantly increases and tumour growth is reduced in vivo (Hendrick et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hendrick et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HDAC7 binds near TSS and to SEs of oncogenes and contributes to their transcriptional regulation.

    “HDAC7 binds near TSS and to SEs of oncogenes and contributes to their transcriptional regulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Caslini et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevenostan exhibits activity in the nanomolar range and acts synergistically with bortezomib in inducing cell death.

    “Elevenostan exhibits activity in the nanomolar range and acts synergistically with bortezomib, an anti-myeloma drug, in inducing cell death (Mostofa et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mostofa et al., 2021

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Downregulation of HDAC11 in lymph nodes leads to increased migration and colonization of distal sites, resulting in distal metastasis.

    “HDAC11 is important for tumorigenesis and growth in lymph nodes, but its downregulation in the lymph nodes leads to increased migration and colonization of distal sites, resulting in distal metastasis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Leslie et al., 2019

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    HDAC4 is primarily thought to have a tumor-promoting role.

    “While HDAC4 is primarily thought to have a tumor-promoting role, HDAC5 and HDAC7 are associated with both pro-tumorigenic and tumor suppressive functions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Repression of Lkb1 affects Ampk activation and glycolysis.

    “Repression of Lkb1 thereby affects Ampk activation and glycolysis (Bi et al., 2021).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bi et al., 2021

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RRM2 is associated with poor disease-free survival in breast cancer and can affect cancer proliferation, angiogenesis, and invasiveness.

    “This gene is associated with poor diseasefree survival in breast cancer and it can affect cancer proliferation, angiogenesis, and invasiveness (Zhang et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhang et al., 2014

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    HDAC7 plays an important role in maintaining stemness properties.

    “HDAC7 also plays an important role in maintaining stemness properties.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Class IIa HDACs regulate proliferation, cell cycle, metabolism, senescence, and invasion/metastasis in cancer cells.

    “Class IIa HDACs regulate proliferation, cell cycle, metabolism, senescence, and invasion/metastasis in cancer cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    HDAC9 is involved in invasion/metastasis, proliferation and response to treatments.

    “HDAC9 is involved in invasion/metastasis, proliferation and response to treatments.”
    Quote in the paperNot a substantial claim
91 of 91

  • The paper relies on this without support.

    The epigenome of cancer cells can in principle be reversed.

    “Unlike genomic mutations, the epigenome of cancer cells can in principle be reversed.”

  • The paper relies on this without support.

    Transcriptional control is a key function in cancer and is controlled by rearrangement of the epigenome.

    “Transcriptional control is a key function in this context and is controlled by the rearrangement of the epigenome.”

  • The paper relies on this without support.

    DNA mutations must hijack cellular functions to sustain the spread of mutant genomes.

    “Mutations of DNA are the drivers of the tumorigenic process, but mutations must be able to hijack cellular functions to sustain the spread of mutant genomes.”

  • The paper relies on this without support.

    The complexity of the epigenetic machinery has frustrated enthusiasm for epigenetic drugs.

    “Unfortunately, the complexity of the epigenetic machinery has frustrated this enthusiasm.”

  • The paper relies on this without support.

    HDAC activities need to be hijacked to maintain the transformation state.

    “i) their activities need to be hijacked to maintain the transformation state”

  • The paper relies on this without support.

    HDACs are directly responsible for transformation events.

    “ii) they are directly responsible for transformation events.”

  • The paper relies on this without support.

    HDAC5 acts as a senescence antagonist.

    “Similarly, HDAC5 may also act as a senescence antagonist.”

  • The paper relies on this without support.

    HDAC1 and HDAC3 are involved in maintaining the high expression of HDAC7.

    “HDAC1 and HDAC3 appear to be involved in maintaining the high expression of HDAC7 in an undetermined manner.”

  • The paper relies on this without support.

    HDACs are frequently implicated in cancer.

    “Although frequently implicated in cancer, they do not always involve epigenetic targets.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Histone modifications are dynamically regulated by coordinated enzyme systems referred to as writers, erasers, and readers, which deposit, remove, or recognize specific epigenetic marks.

    “Histone modifications are dynamically regulated by coordinated enzyme systems commonly referred to as “writers,” “erasers,” and “readers,” which respectively deposit, remove, or recognize specific epigenetic marks (Kelly et al., 2018; Brancolini et al., 2022).”

    From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Brancolini et al., 2022

    The Introduction describes histone modifications as rapidly reversible and identifies acetyltransferases and deacetylases as opposing enzymes that add and remove acetylation. It does not describe enzymes that recognize marks or present the full “writers, erasers, and readers” framework. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • BRD4097 is described as HDAC3-selective but listed with four targets

    Minor

    The text calls BRD4097 an HDAC3-selective inhibitor, whereas the figure lists HDAC1, HDAC2 and HDAC8 alongside HDAC3 as its targets. No distinction between those listed targets is provided.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Gil, 2016, Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice, Disease Models & Mechanisms, 9, 1483

Cited by

Sorted by citations

Related

Authors
Brancolini, C., Gagliano, T., & Minisini, M.
Affiliations
University of Udine (IT)
Corresponding author
Brancolini, Claudio
ORCID
Venue
Pharmacology & Therapeutics
Publisher
Elsevier BV
Published
2022-10
Volume
238
Pages
108190
ISSN
0163-7258 (ISSN-L)
DOI
10.1016/j.pharmthera.2022.108190
OpenAlex
W4226377997
Cited by
55
References
229
Citations by year
2026: 9 · 2025: 20 · 2024: 14 · 2023: 9 · 2022: 3
FWCI
1.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacology & Therapeutics (publishedVersion, cc-by-nc-nd)
  • SSRN Electronic Journal (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Research Information System (University of Udine) (submittedVersion, cc-by)
Funders
  • Interreg
  • European Commission
  • Associazione Italiana per la Ricerca sul Cancro
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
histone deacetylase, epigenetic plasticity, cancer cells, epigenetic therapy, transcriptional regulation, epigenetic drugs, selective targeting, tumor microenvironment
MeSH terms
Histone Deacetylases, Humans, DNA Methylation, Epigenesis, Genetic, Epigenomics, Tumor Microenvironment, Carcinogenesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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