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

In the paper

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the use of HDACIs in Cancer Terminated (137) Active not recruiting (60) Recruiting (80) Completed (351) Unknown (50) Withdrawn (32) Phase 1 (424) Phase 2 (387) Phase 3 (30) Phase 4 (3)”

What the sources say

• Not checked yetcites https://www.clinicaltrials.gov

In the paper

“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).”

What the sources say

• Not checked yetcites Fukumoto et al., 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Li et al., 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Rother et al., 2020

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Tang et al., 2019

In the paper

“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).”

What the sources say

• Not checked yetcites Mohanty et al., 2019

In the paper

“Although Sall4 is required for primary tumor growth, loss of Sall4 results in increased metastatic burden.”

What the sources say

• Not checked yetcites Diener et al., 2021 source

In the paper

“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).”

What the sources say

• Not checked yetcites Pflum, Tong, Lane, & Schreiber, 2001
• Not checked yetcites Citro, Miccolo, Meloni, & Chiocca, 2015

In the paper

“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).”

What the sources say

• Not checked yetcites Shi et al., 2004 source

In the paper

“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).”

What the sources say

• Not checked yetcites Mani et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Nagarajan et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Min et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Bahl et al., 2021

In the paper

“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).”

What the sources say

• Not checked yetcites http:// www.cbioportal.org

In the paper

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

What the sources say

• Not checked yetcites Papachristou et al., 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Diener et al., 2021 source

In the paper

“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).”

What the sources say

• Not checked yetcites Millard et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Yates et al., 2017
• Not checked yetcites Pereira et al., 2016

In the paper

“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).”

What the sources say

• Not checked yetcites Ny et al., 2021

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Kumar et al., 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Pili et al., 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Hu et al., 2003

In the paper

“These partners are fundamental for the stabilization of HDAC3 and the maturation of catalytic activity (Emmett & Lazar, 2019).”

What the sources say

• Not checked yetcites Emmett & Lazar, 2019 source

In the paper

“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).”

What the sources say

• Not checked yetcites Alvarez et al., 2018

In the paper

“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.”

What the sources say

• Not checked yetcites Venturutti et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Jamaladdin et al., 2014

In the paper

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

What the sources say

• Not checked yetcites Hicks et al., 2021

In the paper

“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”

What the sources say

• Not checked yetcites Hicks et al., 2020

In the paper

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

What the sources say

• Not checked yetcites Yoon et al., 2003

In the paper

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

What the sources say

• Not checked yetcites Wang et al., 2016

In the paper

“Therefore, HDAC3 can control DNMT1 levels in two different ways: i) directly by deacetylating it and ii) indirectly by stabilizing MYC.”

In the paper

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

What the sources say

• Not checked yetcites Harada et al., 2017

In the paper

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

What the sources say

• Not checked yetcites Sun et al., 2013

In the paper

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

What the sources say

• Not checked yetcites Zhang et al., 2017

In the paper

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

What the sources say

• Not checked yetcites Ji et al., 2019

In the paper

“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).”

What the sources say

• Not checked yetcites Constantinidou et al., 2019

In the paper

“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).”

What the sources say

• Not checked yetcites Bhaskara et al., 2010

In the paper

“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.”

What the sources say

• Not checked yetcites Mondello et al., 2020

In the paper

“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.”

What the sources say

• Not checked yetcites Blattner et al., 2017

In the paper

“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.”

What the sources say

• Not checked yetcites Bhaskara et al., 2010

In the paper

“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.”

What the sources say

• Not checked yetcites Deng et al., 2019

In the paper

“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.”

What the sources say

• Not checked yetcites Mir et al., 2021

In the paper

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

What the sources say

• Not checked yetcites Yan et al., 2018

In the paper

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

What the sources say

• Not checked yetcites Chiappinelli et al., 2015 source

In the paper

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

What the sources say

• Not checked yetcites Nishimoto et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Mondello et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Castañeda et al., 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Broughm et al., 2012
• Not checked yetcites Haarhuis et al., 2014 source
• Not checked yetcites Singh et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Dowsett et al., 2019

In the paper

“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).”

What the sources say

• Not checked yetcites Wang et al., 2016

In the paper

“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).”

What the sources say

• Not checked yetcites Balasubramanian et al., 2008 source

In the paper

“In neuroblastoma, HDAC8 correlates with poor overall survival, and its knockout leads to increased cell differentiation and cell cycle arrest (Oehme et al. , 2009).”

What the sources say

• Not checked yetcites Oehme et al., 2009

In the paper

“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).”

What the sources say

• Not checked yetcites Hu et al., 2000
• Not checked yetcites Lee et al., 2006
• Not checked yetcites Somoza et al., 2004 source

In the paper

“Missense mutations in HDAC8 are responsible for Cornelia de Lange Syndrome (CdLS) and associated spectrum disorders.”

What the sources say

• Not checked yetcites Dowsett et al., 2019

In the paper

“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).”

What the sources say

• Not checked yetcites Qi et al., 2015

In the paper

“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).”

What the sources say

• Not checked yetcites Buggy et al., 2000 source
• Not checked yetcites Hu et al., 2000

In the paper

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

What the sources say

• Not checked yetcites Hua et al., 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Maertens et al., 2019 source

In the paper

“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).”

What the sources say

• Not checked yetcites Avagliano et al., 2020
• Not checked yetcites Watrin et al., 2016

In the paper

“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).”

What the sources say

• Not checked yetcites Hill et al., 2016

In the paper

“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).”

What the sources say

• Not checked yetcites Gantt et al., 2006

In the paper

“In this scenario HDAC8 is an important player since its inhibition suppresses cancer metastasis and chemotherapy resistance.”

What the sources say

• Not checked yetcites Tang et al., 2020

In the paper

“On the other hand, simultaneous treatment with both inhibitors increases TP53 acetylation and activity.”

What the sources say

• Not checked yetcites Long et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Wu et al., 2020

In the paper

“An epigenetic regulation previously observed for others class IIa and possibly mediated by MEF2 TFs (Clocchiatti et al., 2015).”

What the sources say

• Not checked yetcites Clocchiatti et al., 2015

In the paper

“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.”

In the paper

“HDAC8 can bind the SMAD3/4 complex and supplies its epigenetic influence, by creating a repressive environment at the SIRT7 promoter.”

What the sources say

• Not checked yetcites Tang et al., 2020

In the paper

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

What the sources say

• Not checked yetcites Zhang et al., 2017

In the paper

“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.”

What the sources say

• Not checked yetcites Emmons et al., 2019

In the paper

“Indeed, their interaction increases after treatment with quizartinib and leads to inactivation of TP53, which allows leukemia cell survival.”

What the sources say

• Not checked yetcites Long et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Brancolini et al., 2021
• Not checked yetcites Di Giorgio & Brancolini, 2016

In the paper

“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).”

What the sources say

• Not checked yetcites Xu et al., 2020

In the paper

“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).”

What the sources say

• Not checked yetcites Xu et al., 2020

In the paper

“Mass spectrometry-based phosphoproteomic analysis revealed that HDAC8 regulates multiple signaling pathways, of which the MAPK pathway is important for resistance.”

What the sources say

• Not checked yetcites Emmons et al., 2019

In the paper

“In contrast, in breast cancer cells, SerRS acetylation and nuclear translocation are strongly inhibited.”

What the sources say

• Not checked yetcites Zhao et al., 2021

In the paper

“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.”

What the sources say

• Not checked yetcites Thole et al., 2017

In the paper

“Moreover, pharmacological inhibition of TGF-β can restore TCA cycle enzymes expression and reduce tumour growth in vivo.”

What the sources say

• Not checked yetcites Nam et al., 2021

In the paper

“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.”

What the sources say

• Not checked yetcites Nam et al., 2021

In the paper

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

What the sources say

• Not checked yetcites Nam et al., 2021

In the paper

“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).”

What the sources say

• Not checked yetcites Hendrick et al., 2017

In the paper

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

What the sources say

• Not checked yetcites Caslini et al., 2019

In the paper

“Elevenostan exhibits activity in the nanomolar range and acts synergistically with bortezomib, an anti-myeloma drug, in inducing cell death (Mostofa et al., 2021).”

What the sources say

• Not checked yetcites Mostofa et al., 2021

In the paper

“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.”

What the sources say

• Not checked yetcites Leslie et al., 2019

In the paper

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

In the paper

“Repression of Lkb1 thereby affects Ampk activation and glycolysis (Bi et al., 2021).”

What the sources say

• Not checked yetcites Bi et al., 2021

In the paper

“This gene is associated with poor diseasefree survival in breast cancer and it can affect cancer proliferation, angiogenesis, and invasiveness (Zhang et al., 2014).”

What the sources say

• Not checked yetcites Zhang et al., 2014

In the paper

“HDAC7 also plays an important role in maintaining stemness properties.”

In the paper

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

In the paper

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