Acetylation: a new target for protein degradation in cancer

May combine two claims.

Decreased MST1 leads to decreased downstream YAP phosphorylation and suppressed YAP nuclear translocation.

“This has the intuitive effect of decreasing downstream YAP phosphorylation and suppressing YAP nuclear translocation [108].”

• cites [108] sourceDisputed

  The Introduction says that MST1/2 inactivation is associated with decreased YAP phosphorylation but increased nuclear localization of YAP. Thus, the phosphorylation part is supported, while the claimed suppression of YAP nuclear translocation is contrary to the source. (LLM, conf=0.93)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

Approved KDAC inhibitors are largely non-selective because there are only about 18 known acetyltransferases and 18 known deacetylases for thousands of acetylation sites.

“The approved KDAC inhibitors are largely non-selective, as there are only ~18 known acetyltransferases and ~18 known deacetylases for thousands of acetylation sites [25–27].”

• cites [25] sourcePartly supported

  The Lysine deacetylases section says the human genome encodes 18 KDACs, and the Introduction reports thousands of acetylation sites. But the Lysine acetyltransferases section says the number of bona fide KATs is unclear and identifies 13 well-characterized KATs, not approximately 18. The Therapeutic targeting of acetylation section lists approved KDAC inhibitors but does not say they are largely non-selective or attribute their selectivity to the number of enzymes and sites. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [26] sourceNot checked — no full text of the source
• cites [27] sourceNot checked — no full text of the source

May combine two claims.

High glucose concentrations result in ACLY acetylation at K540, K546, and K554, which block ubiquitination at these sites and increase ACLY stability by preventing UBR4-mediated degradation.

“High glucose concentrations result in ACLY acetylation at three lysine residues (K540, K546, K554), which function to block ubiquitination at these sites and thus increase ACLY stability by preventing ubiquitin-mediated degradation via E3 ligase UBR4 [42].”

• cites [42] sourceSupported

May combine two claims.

One of the most commonly used PPI inhibitors and E3 ligase ligands is derived from a PTM-bearing peptide, hydroxylated HIF-1α, proving the possibility of developing inhibitors for this type of interaction.

“One of the most commonly used PPI inhibitors and E3 ligase ligands is derived from a PTM bearing peptide, hydroxylated HIF-1α [33], thus proving the possibility of developing inhibitors for this type of interaction.”

• cites [33] sourcePartly supported

  The Introduction (page not available) describes proline hydroxylation of HIF-1α as a post-translational modification that enables pVHL binding. The “HIF-1α degradation pathway” section (page not available) reports hydroxyproline-based inhibitors of that interaction and says pVHL ligands have been useful in PROTAC development. It does not establish that a ligand was derived from a hydroxylated HIF-1α peptide or that it is among the most commonly used PPI inhibitors and E3 ligase ligands. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

PPIs are highly specific, especially those dependent on acetylated isoforms, and are attractive therapeutic targets.

“PPIs are highly specific (especially PPIs dependent on acetylated isoforms [17]) and are thus attractive, albeit challenging, therapeutic targets[18].”

• cites [17] sourceSupported
• cites [18] sourceNot checked — no full text of the source

May combine two claims.

Development of an acetylation targeting chimera (AceTAC) targeting p53 acetylation has shown promising results, while other attempts to target the p53-Mdm2 interaction have struggled.

“development of an acetylation targeting chimera (AceTAC) targeting p53 acetylation has shown promising results, while other attempts to target the p53-Mdm2 interaction thus far have struggled [39–41].”

• cites [39] sourcePartly supported

  In the main text (page not specified), the paper reports resistance to MDM2 inhibitors and says tumors overexpressing MDM2 and MDMX remain an unmet medical need, supporting the claim that efforts to target this interaction have faced difficulties. It does not discuss AceTAC or results from targeting p53 acetylation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [40] sourcePartly supported

  The Introduction and Conclusions (page not available) report that the AceTAC compound MS78 acetylated the p53Y220C mutant and suppressed growth of cancer cells carrying that mutation, supporting the promising-results portion. The paper does not report that attempts to target the p53–Mdm2 interaction have struggled; its discussion of Mdm2 concerns gene expression, not that interaction. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [41] sourcePartly supported

  The Introduction and Conclusions (page not provided) report that p53Y220C AceTACs induced acetylation and suppressed growth in cancer cell lines, supporting the description of promising results. The cited paper does not address whether attempts to target the p53–Mdm2 interaction have struggled; a search for Mdm2 found no relevant passage. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

ACLY acetylation enhances cell proliferation through increased ACLY function, resulting in increased acetyl-CoA production and lipogenesis.

“ACLY acetylation enhances cell proliferation through an increase in ACLY function, resulting in increased acetyl-CoA production and lipogenesis [42,43].”

• cites [42] sourceSupported
• cites [43] sourcePartly supported

  The introduction (pp. 1–2) reports that ACLY acetylation increases protein stability and promotes lipid synthesis and cell proliferation in lung cancer cells; the paper also finds increased lipid accumulation in hepatocytes. It explains that ACLY produces acetyl-CoA for lipogenesis (p. 1), but does not show that acetylation increases acetyl-CoA production. The proliferation finding is reported from a previous study, not demonstrated in this paper. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

AceTAC MS78 targets disease-relevant p53 mutant p53Y220C and recruits p300 to induce p53 acetylation and subsequent stabilization and activation to promote tumor-suppressor activity.

“AceTAC MS78 targets disease-relevant p53 mutant p53Y220C and recruits p300 to induce p53 acetylation and subsequent stabilization and activation to promote tumor-suppressor activity of p53 [40].”

• cites [40] sourcePartly supported

  The Conclusions and §2.2 report that MS78 brings p53Y220C together with p300 and induces its acetylation. Section 2.2 also reports stabilization of p53Y220C, while the Introduction and Conclusions describe p53-dependent growth suppression. However, the paper presents stabilization as an effect of MS78 binding; it does not establish the claimed sequence in which acetylation leads to subsequent stabilization. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

AceTACs recruiting GCN5 to p53 result in different acetylation sites being edited and distinct transcriptional activation from p300 recruitment.

“AceTACs recruiting GCN5 to p53 have resulted in different acetylation sites being edited and distinct transcriptional activation from p300 recruitment [51].”

• cites [51] sourceSupported

May combine two claims.

Various KDAC inhibitors have been approved by the FDA, such as vorinostat and romidepsin, but there are currently no approved KAT inhibitors.

“Various KDAC inhibitors [19] have been approved by the FDA such as vorinostat [20] (commonly known as SAHA) and romidepsin [21], but there are currently no approved KAT inhibitors [22–24].”

• cites [19] sourceSupported
• cites [20] sourcePartly supported

  The Introduction identifies vorinostat as SAHA and an HDAC inhibitor, supporting the portion attached to citation [20]. Our copy does not state that vorinostat was FDA-approved; the Discussion instead describes further investigation in a phase 2b trial. The separate citations for romidepsin and KAT inhibitors are not assessed here. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [21] sourceSupported

May combine two claims.

ACLY acetylation at these sites is upregulated in various lung cancers, indicating that tumorigenic mechanisms could take advantage of acetylation-mediated aberrant ACLY function to fuel growth.

“ACLY acetylation at these sites is upregulated in various lung cancers- indicating that tumorigenic mechanisms could be taking advantage of acetylation-mediated aberrant ACLY function to fuel growth [42].”

• cites [42] sourceSupported

May combine two claims.

DOT1L drives expression of genes associated with EMT in breast cancer and is a key regulator of hematopoiesis, making it a therapeutic target in MLL-rearranged leukemias.

“DOT1L drives the expression of genes associated with epithelial-mesenchymal transition (EMT) in breast cancer [79] and is also a key regulator of hematopoiesis [80], making it a therapeutic target in MLL-rearranged leukemias [81].”

• cites [79] sourceSupported
• cites [80] sourceNot checked — no full text of the source
• cites [81] sourceSupported

May combine two claims.

Patient samples exhibited higher levels of GLDC and lower levels of GLDCK514Ac compared to non-tumor tissues.

“patient samples exhibited higher levels of GLDC and lower levels of GLDCK514Ac when compared to non-tumor tissues [73].”

• cites [73] sourceSupported

May combine two claims.

Mutating all six ELF5 acetylation sites to glutamine (6KQ) decreases ELF5 stability, and mutating them to non-acetylatable lysine (6KR) reverses this.

“When all of these residues were mutated to acetyl-lysine mimicking glutamine residues (6KQ), ELF5 displayed a significant decrease in stability which was reversed by mutation to non-acetylatable lysine mimic residues (6KR) (Figure 3D) [85].”

• cites [85] sourceSupported

May combine two claims.

GLDCK514Ac-mediated degradation downregulates glycine catabolism and downstream synthesis of glycine-related metabolites (e.g., pyrimidines) when expressed in glioma cells, and inhibits glioma cell proliferation and tumorigenesis.

“GLDCK514Ac-mediated degradation was thus found to downregulate glycine catabolism and the downstream synthesis of glycine-related metabolites (e.g. pyrimidines) when expressed in glioma cells, as well as to inhibit glioma cell proliferation and tumorigenesis [73].”

• cites [73] sourceSupported

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

The connection between nutrient supplementation and acetylation of metabolic proteins exemplified by BCAT2, PHGDH, and GS has been shown before with ACLY, MATIIα, ECHS1, and splicing factors.

“The connection between nutrient supplementation and acetylation of metabolic proteins exemplified by BCAT2, PHGDH, and GS is a concept that has been shown before with ACLY [42], methionine adenosyltransferase IIα (MATIIα) [67], enoyl-CoA hydratase-1 (ECHS1) [68], and splicing factors that function to regulate glucose metabolism [69]”

• cites [42] sourceSupported
• cites [67] sourceSupported
• cites [68] sourceSupported

May combine two claims.

GNPATK128Ac is responsible for ACAT1-mediated oncogenic phenotypes in HCC and several other cancers, consisting of increases in lipogenesis and proliferation.

“GNPATK128Ac is therefore responsible for ACAT1-mediated oncogenic phenotypes in hepatocellular carcinoma (HCC) and several other cancers, which consist of increases in lipogenesis and proliferation [58,60].”

• cites [58] sourceNot checked — no full text of the source
• cites [60] sourcePartly supported

  The “ACAT1 and hepatocellular carcinoma” section links ACAT1-mediated GNPAT K128 acetylation to lipogenesis and HCC xenograft growth. The paper discusses ACAT1 in other cancers, but does not attribute their oncogenic phenotypes to GNPAT K128 acetylation; it describes different mechanisms for them. It reports tumor growth rather than directly establishing increased HCC cell proliferation through this pathway. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

DOT1LK358Ac positively correlates with progression, severity, and metastasis in in vitro, mouse, and patient tissue models of colorectal cancer but has yet to be studied extensively in other relevant settings.

“DOT1LK358Ac was accordingly shown to positively correlate with progression, severity and metastasis in in vitro, mouse, and patient tissue models of colorectal cancer but has yet to be studied extensively in other relevant settings [78].”

• cites [78] sourcePartly supported

  The Results sections on CRC stage and metastasis report higher DOT1L(K358) acetylation in more advanced CRC cell lines and patient tumors, and the in vivo Results report greater lung metastasis in the mouse model under acetylation-favoring conditions. Our copy does not establish the broader claim that DOT1L(K358) acetylation has yet to be studied extensively in other relevant settings. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

GLDC is a mitochondrial enzyme that catalyzes the first step of glycine catabolism and is hyperactive in various cancers.

“glycine decarboxylase (GLDC), a mitochondrial enzyme that catalyzes the first step of glycine catabolism and is hyperactive in various cancers [70–72].”

• cites [70] sourcePartly supported

  The Results and Discussion section, “Hepatocellular carcinoma has high expression and metabolic flux of GCS” (page unavailable), identifies GLDC as a glycine-cleavage-system subunit and reports high GLDC expression in hepatocellular carcinoma and renal cancer. The paper also reports high glycine-cleavage flux in hepatocellular carcinoma, but high expression does not establish that GLDC is hyperactive across various cancers. Our copy describes mitochondrial glycine catabolism through the system without explicitly identifying GLDC’s reaction as its first step. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [71] sourcePartly supported

  In “GLDC Is a Metabolic Oncogene” (page not provided), the paper says GLDC catalyzes the irreversible rate-limiting step of glycine catabolism. In “GLDC and Glycine Metabolism Are Relevant to Human Cancer Patients” (page not provided), it reports increased GLDC expression in many cancers. Our copy does not identify GLDC as mitochondrial or establish that its enzymatic activity is elevated across those cancers; increased expression is not the same measurement. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [72] sourcePartly supported

  The Discussion (p. 9) identifies GLDC as an enzyme in the glycine cleavage system and says it is highly active in different cancer cells. The Introduction (p. 2) also describes its role in glycine breakdown. The paper does not explicitly state that GLDC is mitochondrial or that it catalyzes the first step of glycine catabolism. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

ACAT1 inhibition is broadly applicable to various cancer types but not non-cancerous cells.

“Notably, ACAT1 inhibition is broadly applicable to various cancer types but not non-cancerous cells [61].”

• cites [61] sourceSupported

May combine two claims.

The GNPATK128Ac-FASN interaction results in repression of TRIM21-mediated FASN degradation and subsequent increase in FASN, triglyceride, and fatty acid levels consistent with increased lipogenesis.

“The GNPATK128Ac-FASN interaction resulted in a repression of TRIM21-mediated FASN degradation [59] and a subsequent increase in FASN, triglyceride, and fatty acids levels consistent with an increase in lipogenesis (Figure 2B).”

• cites [59] sourceSupported

May combine two claims.

K75 lies within Sox2's nuclear export signal and is required for Sox2 to interact with Crm1.

“K75 exists within Sox2’s nuclear export signal (NES) and is necessary for Sox2’s ability to interact with nuclear export receptor protein Crm1 [87].”

• cites [87] sourcePartly supported

  The Introduction places K75 within Sox2’s nuclear export signal. Results §§3.1–3.2 link K75 acetylation to nuclear export and show that reduced Sox2 acetylation disrupts its interaction with Crm1. They do not establish that K75 itself is necessary for Sox2 to bind Crm1. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

DOT1L/KMT4 undergoes CBP-mediated acetylation at K358, disrupting the ability of E3 ligase RNF8 to bind and ubiquitinate DOT1L.

“DOT1L/KMT4 undergoes CBP-mediated acetylation at K358, disrupting the ability of E3 ligase RNF8 to bind and ubiquitinate DOT1L (Figure 3B) [78].”

• cites [78] sourceSupported

May combine two claims.

In breast cancer cells and mouse models, ELF5 6KR has little effect on proliferation, while ELF5 6KQ and wild-type ELF5 reduce proliferation via decreased cyclin D1 and increased growth-phase arrest.

“When expressed in breast cancer cells and mouse models, ELF56KR expression had little effect on cell proliferation while ELF56KQ and ELF5WT expression reduced cell proliferation due to a reduction of cyclin D1 and an increase in growth phase arrest [85].”

• cites [85] sourcePartly supported

  The Results sections on proliferation and CCND1 transcription (page unavailable) report that ELF5-6KR did not reduce proliferation, while ELF5-WT and ELF5-6KQ did; both WT and 6KQ also lowered cyclin D1. The reported increase in G1-phase cells is specifically for ELF5-WT in MCF7 cells, not explicitly for ELF5-6KQ, so the claim extends that cell-cycle finding to 6KQ without support. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

BCAT2 is a mitochondrial enzyme involved in BCAA metabolism, which can contribute to pancreatic cancer development and growth.

“Branched-chain amino acid transaminase 2 (BCAT2) is a mitochondrial enzyme involved in branched-chain amino acid (BCAA) metabolism, which can contribute to pancreatic cancer development and growth [64,65].”

• cites [64] sourceCould not verify

  The passages supplied and retrieved under this DOI are labeled “Intracellular sensing of viral genomes and viral evasion” and discuss viral sensing, not the named pancreatic-cancer paper. Searches for BCAT2, BCAA metabolism, and pancreatic cancer growth returned no relevant passage, so our copy cannot verify the claim. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [65] sourceSupported

May combine two claims.

This is a conserved mode of regulation for GS, as CRBN and glutamine can induce degradation of GS in HCC, myeloma, breast cancer, and lung cancer.

“This is a conserved mode of regulation for GS, as CRBN and glutamine can induce degradation of GS in HCC, myeloma, breast cancer, and lung cancer [62].”

• cites [62] sourcePartly supported

  The Results section (“CRL4CRBN directly controls the glutamine-induced degradation of GS,” Figures 2A–C and S1E–S2F) reports glutamine-induced GS loss in Hep3B, myeloma, breast, and lung cancer cell lines. CRBN depletion blunted that loss in Hep3B, myeloma, and lung cells, but CRBN dependence was not directly shown in breast cells; there, the paper reports inhibition by MLN4924, which acts on Cullin-RING ligases more broadly. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

HDAC inhibitors reduce basal-like breast cancer growth, and this effect is partially reversed by KLF5 knockdown.

“Deacetylase inhibitors (HDACi) reduces BLBC growth, a phenotype which is partially reversed upon KLF5 knockdown, leading to the hypothesis that KLF5 acetylation could contribute to BLBC [83].”

• cites [83] sourceSupported

• AssumptionRests on an assumption: KLF5 correlates with poor prognosis in breast cancer.

May combine two claims.

Acetylation-induced change in Sox2 localization increases Sox2 ubiquitination and degradation, and HDAC4 counteracts this.

“Subsequently, Sox2’s acetylation-mediated change in subcellular localization results in an increase of Sox2 ubiquitination and degradation (which is countered by the deacetylase for this mark, HDAC4) (Figure 3E) [87].”

• cites [87] sourceSupported

May combine two claims.

GLDC is acetylated at K514 by ACAT1, which inhibits its enzymatic activity and translocates GLDC into the cytosol where it is recognized by E3 ligase NF-X1 and subsequently degraded.

“GLDC is acetylated at K514 by ACAT1, which inhibits its enzymatic activity as well as translocates GLDC into the cytosol where it is recognized by E3 ligase NF-X1 and subsequently degraded (Figure 2E) [73].”

• cites [73] sourcePartly supported

  The Results sections on ACAT1 and NF-X1 support K514 acetylation, reduced GLDC activity, and NF-X1-mediated ubiquitination and degradation. The cytoplasmic-localization results (Fig. 7) show a shift after rapamycin treatment, but say only that acetylated GLDC *may* translocate from mitochondria to the cytoplasm. The claim presents that acetylation-driven translocation as established. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Acetylation of HMGA2 at K26 directly competes with ubiquitination, stabilizing HMGA2 and increasing occupancy of HMGA2 target promoter regions upstream of cyclin A and SOX2.

“Acetylation of HMGA2 at K26 directly competes with ubiquitination, thus stabilizing HMGA2 and increasing occupancy of HMGA2 target promoter regions upstream of cyclin A and SOX2 (Figure 3A) [77].”

• cites [77] sourceSupported

May combine two claims.

Under BCAA-deprived conditions, BCAT2 becomes acetylated at K44 and displays a remarkably decreased half-life.

“Under BCAA-deprived conditions, BCAT2 becomes acetylated at K44 and displays a remarkably decreased half-life (Figure 2D) [66].”

• cites [66] sourceSupported

May combine two claims.

HMGA2 acetylation is mediated by PCAF, a downstream target of Akt signaling, demonstrating crosstalk of acetylation-mediated degradation with phosphorylation signaling cascades.

“Further, HMGA2 acetylation was mediated by the acetyltransferase PCAF, a downstream target of the Akt signaling pathway, demonstrating the crosstalk of acetylation-mediated degradation with phosphorylation signaling cascades [77].”

• cites [77] sourcePartly supported

  The Results section reports that PCAF acetylates HMGA2 and that Akt signaling increases PCAF phosphorylation and HMGA2 acetylation. But the Results section on HMGA2 stability says acetylation blocks ubiquitination and proteasomal degradation, rather than mediating degradation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Acetylation of KLF5 at K369 reduces its interaction with BAP1, promoting KLF5 ubiquitination and degradation.

“It was subsequently discovered that acetylation of KLF5 at K369 hindered its ability to interact with cognate deubiquitinase (DUB) BAP1, promoting its ubiquitination and degradation (Figure 3C) [83].”

• cites [83] sourceSupported

May combine two claims.

MOB1 is acetylated at K11 by CBP, which interrupts its interaction with E3 ligase Praja2 and stabilizes MOB1.

“LATS1 co-activator MOB1 is acetylated at K11 by CBP which interrupts MOB’s interaction with E3 ligase Praja2 and stabilizes the protein (Figure 5) [107].”

• cites [107] sourceSupported

May combine two claims.

SIRT7 inhibition in HCC mouse models is linked to reduced tumor volume, increased MST1 stability, increased cytoplasmic YAP, and reduced expression of YAP target genes.

“SIRT7 inhibition in HCC mouse models was therefore not only linked to reduced tumor volume; it was also linked to increased MST1 stability, YAP in the cytoplasmic fraction, and reduced expression of YAP target genes [108].”

• cites [108] sourcePartly supported

  The Results section (‘SIRT7 inhibition suppresses HCC growth via MST1/YAP axis’; page unavailable) reports that 2800Z inhibited growth of transplanted tumors, increased MST1 protein, decreased nuclear YAP localization, and reduced YAP target-gene transcription in vivo. Reduced MST1 ubiquitination and YAP sequestration in the cytoplasmic fraction were shown in HCC cells, not in the mouse tumors; increased MST1 stability and cytoplasmic YAP in the mouse models are therefore not established. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Stabilized acetylated AFP increases transcription of metastatic proteins, promoting HCC migration.

“The stabilized, acetylated AFP is therefore more able to complete its pro-oncogenic functions: i.) bind and inhibit phosphatase PTEN to increase levels of p-AKT and promote HCC proliferation, ii.) increase transcription of metastatic proteins to increase HCC migration, and iii.) bind caspase 3 and block its pro-apoptotic function in the presence of oxidative stress to suppress apoptosis (Figure 4B”

• cites [98] sourcePartly supported

  Section 3.6 (page unavailable) reports that acetylated AFP increased metastasis-related protein levels and HCC-cell migration compared with an acetylation-deficient mutant. The Discussion also says acetylation stabilizes AFP. The paper measures protein levels, however, and does not establish that AFP increases their transcription. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

SIRT7 deacetylates MST1 in HCC, leading to increased MST1 degradation.

“SIRT7 has recently been linked to the deacetylation of MST1 in HCC and the resulting increase in MST1 degradation (Figure 5) [108].”

• cites [108] sourceSupported

May combine two claims.

YAP contains a phosphodegron, so decreased YAP phosphorylation leads to YAP accumulation and nuclear translocation.

“YAP bears a phosphodegron so decreased YAP phosphorylation leads to YAP accumulation and eventual translocation into the nucleus where it drives transcription of tumor-promoting genes (Figure 5) [106].”

• cites [106] sourcePartly supported

  The Abstract (page unavailable) identifies a YAP phosphodegron and says its phosphorylation promotes YAP degradation; it separately links Ser127 phosphorylation to cytoplasmic retention. The Spatial and temporal regulation of YAP section (page unavailable) likewise treats degradation and nuclear–cytoplasmic localization as distinct mechanisms. The source therefore supports the broad effect of reduced phosphorylation on YAP accumulation and nuclear activity, but not the sentence’s implication that phosphodegron phosphorylation itself controls nuclear translocation or its specific claim about transcription of tumor-promoting genes. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

AFP 3KR exhibits enhanced ubiquitination and degradation.

“AFP3KR, accordingly, exhibits enhanced ubiquitination and degradation [98].”

• cites [98] sourceSupported

May combine two claims.

Stabilized acetylated AFP binds and inhibits PTEN, increasing p-AKT levels and promoting HCC proliferation.

“The stabilized, acetylated AFP is therefore more able to complete its pro-oncogenic functions: i.) bind and inhibit phosphatase PTEN to increase levels of p-AKT and promote HCC proliferation, ii.) increase transcription of metastatic proteins to increase HCC migration, and iii.) bind caspase 3 and block its pro-apoptotic function in the presence of oxidative stress to suppress apoptosis (Figure 4B”

• cites [98] sourceSupported

May combine two claims.

SIRT1 overexpression deacetylates p62 and hinders the p62-KEAP1 interaction, allowing increased HCC tumor volume associated with increased phosphorylated mTOR.

“Conversely, SIRT1 overexpression deacetylated p62 and hindered the p62-KEAP1 interaction, allowing for an increase in HCC tumor volume, which was connected to increased levels of phosphorylated mTOR [103].”

• cites [103] sourcePartly supported

  The Results section reports that Sirt1 deacetylates p62 at K295, disrupting its interaction with Keap1; Sirt1 knockdown also reduced phosphorylated mTOR in HCC cells. The paper reports lower liver-tumor burden and p-mTOR in Sirt1-knockout mice, but does not show that Sirt1 overexpression increased HCC tumor volume together with p-mTOR. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Stabilized acetylated AFP binds caspase 3 and blocks its pro-apoptotic function under oxidative stress, suppressing apoptosis.

“The stabilized, acetylated AFP is therefore more able to complete its pro-oncogenic functions: i.) bind and inhibit phosphatase PTEN to increase levels of p-AKT and promote HCC proliferation, ii.) increase transcription of metastatic proteins to increase HCC migration, and iii.) bind caspase 3 and block its pro-apoptotic function in the presence of oxidative stress to suppress apoptosis (Figure 4B”

• cites [98] sourceSupported

May combine two claims.

Expression of AFP 3KR mutant is comparable to control AFP knockout cells, indicating that AFP acetylation is responsible for these phenotypes.

“In all of these examples, expression of a AFP3KR mutant was comparable to control AFP knockout cells, indicating that the acetylation of AFP was responsible for these phenotypes [98].”

• cites [98] sourcePartly supported

  Sections 3.5–3.7 report that AFP-3KR-expressing cells resembled control cells in proliferation, migration, invasion, and apoptosis assays, and attribute the wild-type AFP effects to acetylation. But the paper calls the comparators control cells, not AFP-knockout cells; Methods §2.1 identifies HLE as AFP-negative and HepG2 as AFP-positive. Page numbers were not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Stathmin 1 is acetylated at K9 by PCAF and deacetylated by SIRT2; this acetylation reduces its interaction with E3 ligase RLIM, inhibiting its ubiquitination and degradation.

“Stathmin 1 is acetylated at K9 (modulated by PCAF and SIRT2), which reduces its interaction with E3 ligase RLIM and therefore inhibits ubiquitination and degradation of stathmin 1 (Figure 4A) [94].”

• cites [94] sourceSupported

May combine two claims.

Higher AFP expression and AFP acetylation correlate with poor prognosis in HCC patient tissue samples.

“Higher AFP expression and AFP acetylation also correlated with poor prognosis in HCC tissue samples from patients [97,98], indicating that the AFP acetylated isoform could be an effective therapeutic target for HCC.”

• cites [97] sourcePartly supported

  Section 5.2 (page unavailable) states that elevated serum AFP is associated with poorer prognosis in HCC patients. It does not establish the claimed association for AFP expression or acetylation measured in patient tissue samples. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [98] sourcePartly supported

  Section 3.8 reports that high levels of acetylated AFP in 70 HCC tissue specimens were associated with poorer progression-free and overall survival. The paper does not report a separate tissue-based prognosis analysis for overall AFP expression; its discussion of unmodified AFP as a prognostic marker concerns serum levels, not tissue samples. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

HDAC2 deacetylates SmD2, reversing this phenotype and allowing stabilized SmD2 to contribute to HCC proliferation via regulation of exon skipping in mRNA of DNA repair proteins.

“SmD2 deacetylation, catalyzed by HDAC2, reverses this phenotype to allow stabilized SmD2 to contribute to HCC proliferation via the regulation of exon skipping in mRNA of proteins linked to DNA repair [118].”

• cites [118] sourceSupported

May combine two claims.

BTZ-resistant cells use HDAC1-mediated stabilization of HP1γ to increase DNA repair, HP1γ nuclear condensate formation, and chromatin accessibility of DNA repair genes, conferring drug resistance.

“As such, BTZ-resistant cells use HDAC1-mediated stabilization of HP1γ to increase DNA repair, HP1γ’s ability to form nuclear condensates, and chromatin accessibility of genes implicated in DNA repair to confer drug resistance [116].”

• cites [116] sourceSupported

May combine two claims.

MCL1 K40Q displays much lower phosphorylation, making acetylation at K40 an indirect mechanism of stabilization.

“Crosstalk between the acetylation and phosphorylation marks was demonstrated as MCL1K40Q displayed much lower phosphorylation, making acetylation at K40 an indirect mechanism of stabilization [120].”

• cites [120] sourcePartly supported

  The Results section (page not supplied) reports relatively lower S159/T163 phosphorylation in the acetylation-mimetic MCL1 K40Q mutant. The Discussion proposes that K40 acetylation may stabilize MCL1 through reduced phosphorylation and increased USP9X binding, but presents this indirect mechanism as a likely model requiring further analysis, not an established causal pathway. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

YEATS4 3KR reduces tumor size and weight in bladder cancer cell lines and mouse models.

“YEATS43KR also reduced homologous recombination and non-homologous end joining (NHEJ) as well as tumor size/weight when expressed in bladder cancer cell lines and mouse models, indicating that YEATS4 acetylation is crucial for its tumor-promoting activity [114].”

• cites [114] sourceSupported

May combine two claims.

Romidepsin combined with BTZ significantly reduces tumor growth and increases apoptosis compared to BTZ alone in multiple myeloma models.

“HDAC1/2 inhibitor, romidepsin, re-sensitized MM cells in tissue and mouse models to BTZ and when jointly administered with BTZ, significantly reduced tumor growth and increased apoptosis compared to BTZ treatment alone [116].”

• cites [116] sourceSupported

May combine two claims.

p300 acetylates SmD2 at K8, increasing its ubiquitination and decreasing its stability.

“SmD2 becomes acetylated on K8 by p300, which contributes to an increase in ubiquitination and a decrease in stability (Figure 6D) [118].”

• cites [118] sourceSupported

May combine two claims.

A non-acetylatable YEATS4 3KR mutant binds HUWE1 more than wild-type YEATS4, which was confirmed to exist in acetylated form.

“A non-acetylatable YEATS43KR mutant showed increased ability to bind HUWE1 when compared to YEATS4WT (which was confirmed to exist in its acetylated form) [114].”

• cites [114] sourceSupported

May combine two claims.

KAT/KDAC inhibitors exhibit marked effects on histone modifications, potentially altering the entire transcriptional profile of tumor cells and rendering therapeutics non-specific.

“KAT/KDAC inhibitors also exhibit marked effects on histone modifications, potentially inducing changes to the entire transcriptional profile of the tumor cells and further rendering therapeutics non-specific.”

May combine two claims.

Inhibition of the p53/Mdm2 interaction using small molecules stabilizes p53 but does not sufficiently activate it.

“inhibition of the p53/Mdm2 interaction using small molecules stabilizes p53 but does not sufficiently activate it [47].”

• cites [47] sourceNot checked — no full text of the source

May combine two claims.

These enzymes each regulate hundreds of acetylation marks, making selective targeting of specific sites difficult.

“These enzymes are therefore responsible for the regulation of hundreds of acetylation marks each, making it difficult to selectively target specific sites.”

May combine two claims.

Acetylated lysine drives the interactions, providing a starting point for molecular recognition and ligand development using acetylated lysine bio-isosteres.

“Acetylated lysine drives the interactions, thus providing a starting point for molecular recognition and ligand development using acetylated lysine bio-isosteres [32].”

• cites [32] sourceNot checked — no full text of the source

May combine two claims.

These studies provide proof of concept for acetylation editing approaches for protein homeostasis modulation and new therapeutic strategies for tumor suppressor activation.

“These studies provide proof of concept for acetylation editing approaches for protein homeostasis modulation as well as new therapeutic strategies for tumor suppressor activation.”

May combine two claims.

KDAC inhibitors often show sub-optimal efficacy in the clinic, especially in solid tumors, and cause side effects such as blood thinning, cardiac abnormalities, and nausea/vomiting.

“KDAC inhibitors often exhibit sub-optimal efficacy in the clinic (especially when administered to patients with solid tumors) as well as side effects such as blood thinning, cardiac abnormalities, and nausea/vomiting [28].”

• cites [28] sourceNot checked — no full text of the source

May combine two claims.

Using heterobifunctional molecules induces long-lasting modifications to the target protein via a transient protein-protein interaction, only slightly perturbing the cellular process and allowing a single heterobifunctional to catalyze modifications on multiple protein copies.

“using heterobifunctional molecules induces long-lasting modifications to the target protein via a transient protein-protein interaction, thus only slightly perturbing the cellular process and allowing for a single heterobifunctional to catalyze modifications on multiple protein copies [36].”

• cites [36] sourceNot checked — no full text of the source

May combine two claims.

These gain-of-function mechanisms fit the stoichiometry constraint and have pronounced phenotypic effects due to the irreversible nature of protein degradation.

“These gain-of-function mechanisms fit the stoichiometry constraint (Box 1) and their effects are phenotypically pronounced due to the irreversible nature of protein degradation.”

May combine two claims.

Upon DNA damage, p53 becomes acetylated at multiple residues within its C-terminal domain to stabilize the protein by directly blocking ubiquitination at acetylated sites and hindering the interaction between p53 and MDM2 to discourage ubiquitination at unacetylated sites.

“upon DNA damage, p53 becomes acetylated at multiple residues within its C-terminal domain to stabilize the protein via directly blocking ubiquitination at acetylated sites as well as hindering the interaction between p53 and MDM2 to discourage ubiquitination at unacetylated sites [47,48].”

• cites [47] sourceNot checked — no full text of the source
• cites [48] sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

The induction of PPIs by acetylation suggests using small molecule inhibitors of acetyl-specific PPIs to modulate homeostasis of cancer-relevant proteins, allowing more selectivity than KAT/KDAC inhibitors.

“The induction of PPIs by acetylation suggests using small molecule inhibitors of acetyl-specific PPIs to modulate homeostasis of cancer relevant proteins, allowing for more selectivity than KAT/KDAC inhibitors.”

• AssumptionRests on an assumption: Broadly targeting acetylation would produce non-selective toxic effects because acetylation is vital for cellular function.

May combine two claims.

This mechanism is associated with breast cancer, where PHGDH and its acetylated proteoform PHGDHK58Ac are significantly upregulated and RNF5 is significantly downregulated.

“This mechanism is associated with breast cancer, where PHGDH and its acetylated proteoform PHGDHK58Ac are significantly upregulated and RNF5 is significantly downregulated [55].”

• cites [55] sourceNot checked — no full text of the source

May combine two claims.

GNPATK128Ac correlates with increased GNPAT stabilization and dimerization by disrupting its ability to bind E3 ligase TRIM21.

“GNPATK128Ac correlates with increased GNPAT stabilization and dimerization by disrupting its ability to bind E3 ligase TRIM21 (Figure 2B) [58].”

• cites [58] sourceNot checked — no full text of the source

May combine two claims.

These ELF5 findings suggest that hyperacetylated cancer-relevant proteins exist and that acetylation has a cancer-relevant role in cell cycle regulation.

“This study indicates the possibility of hyperacetylated cancer-relevant proteins as well as a cancer-relevant role for acetylation in cell cycle regulation.”

May combine two claims.

Acetylation of PHGDH at K58 disrupts the interaction with E3 ligase RNF5, stabilizing PHGDH and allowing increased resistance to oxidative stress, serine levels, and glycine levels.

“Acetylation of PHGDH at this site disrupts the interaction with E3 ligase RNF5, stabilizing PHGDH and allowing for increased resistance to oxidative stress, serine levels, and glycine levels (Figure 2A) [55].”

• cites [55] sourceNot checked — no full text of the source

May combine two claims.

Acetylation of LATS1 at K751 by CBP extends LATS1 half-life and decreases LATS1 ubiquitination.

“Acetylation of K751 by CBP results in an extended LATS1 half-life and decreased LATS1 ubiquitination (Figure 5) [104].”

• cites [104] sourceNot checked — no full text of the source

May combine two claims.

Deacetylation of LHPP by HDAC4 increases its interaction with E3 ligase TRIM21, increases its polyubiquitination, and increases its degradation rate.

“However, when LHPP is deacetylated by HDAC4, LHPP displays increased ability to interact with E3 ligase TRIM21, increased polyubiquitination, and increased rates of degradation (Figure 4C) [100].”

• cites [100] sourceNot checked — no full text of the source

May combine two claims.

Acetylation of stathmin 1 at K9 inhibits its phosphorylation and promotes stathmin 1-mediated microtubule destabilization.

“Acetylation of K9 therefore inhibits stathmin 1 phosphorylation as well as promotes stathmin 1-mediated microtubule destabilization (Figure 4A).”

May combine two claims.

LATS1 K751Q decreases LATS1 phosphorylation and phosphorylation of its downstream target YAP.

“LATS1K751Q thus decreases LATS1 phosphorylation and phosphorylation of its downstream target YAP (Figure 5) [104].”

• cites [104] sourceNot checked — no full text of the source

May combine two claims.

Stabilization of LATS1 K751Q increases nuclear YAP and subsequently increases lung cancer growth and migration in xenograft mouse models.

“The stabilization of LATS1K751Q therefore results in increased YAP in the nuclear fraction and a subsequent increase in lung cancer growth and migration when expressed in xenograft mouse models [104].”

• cites [104] sourceNot checked — no full text of the source

May combine two claims.

These findings reflect a phenomenon of acetylation-phosphorylation crosstalk that is increasingly reported and may present an alternative strategy for targeting phosphorylation effects.

“These findings reflect a phenomenon of acetylation-phosphorylation crosstalk that is being increasingly reported and may present an exciting alternative strategy for targeting the well-known, cancer-relevant effects of phosphorylation.”