A Cancer-Specific Antigen Drives Histone Acetylation by Stabilizing the Acetyltransferases
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Chao Liang
PROVIDER: PXD067966 | iProX | Tue Sep 02 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:<p>SOX2 is not only a pioneer transcription factor with critical roles in stem cell function and cell reprogramming but also a potent oncogene for a multitude of squamous cancers. How SOX2 exerts a potent oncogenic activity in squamous lineage is largely unknown. Here we uncovered SOX2 a potent role in promoting global histone acetylation and super-enhancer formation in esophageal squamous cancer cells. Metabolic analysis revealed a role of SOX2 in suppressing fatty acid synthesis. SOX2 promotes global histone acetylation by two distinct mechanisms: stimulating the expression of a panel of histone acetyltransferases and repressing the expression of ACSL5, which down-regulates fatty acid synthesis and thus channels acetyl-CoA toward histone acetylation. Notably, we found that SOX2 enhanced histone acetylation is required for the formation of most squamous lineage-specific super-enhancers. Our findings provide new explanation for why SOX2 is a powerful cell fate reprogrammer and potent oncogene for squamous lineage cancers.</p>
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Project description:Histone acetylation is a ubiquitous hallmark of transcriptional activity, but whether the link is of a causal or consequential nature is still a matter of debate. In this study we resolve this question. Using both immunoblot analysis and chromatin immunoprecipitation-sequencing (ChIP-seq) in S. cerevisiae, we show that the majority of histone acetylation is dependent on transcription. Loss of histone H4 acetylation upon transcription inhibition is partially explained by depletion of histone acetyltransferases (HATs) from gene bodies, implicating transcription in HAT targeting. Despite this, HAT occupancy alone poorly predicts histone acetylation, suggesting that HAT activity is regulated at a step post-recruitment. Collectively, these data show that the majority of histone acetylation is a consequence of RNAPII promoting both the recruitment and activity of histone acetyltransferases.
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Project description:SOX2 is not only a pioneer transcription factor with critical roles in stem cell function and cell reprogramming but also a potent initiating oncodriver for a multitude of squamous cancers. How SOX2 exerts a potent oncogenic activity in squamous lineage is largely unknown. Here we uncovered a unique role of SOX2 in driving up global histone acetylation in various esophageal squamous cancer cells (ESCCs). Chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated that knockdown of SOX2 in ESCC cells resulted in a global down-regulation of histone acetylation and impaired about half of the super-enhancers. We engineered an ESCC SOX2-dTAG cell line that allowed rapid degradation of SOX2, and subsequent ChIP-seq confirmed a role of SOX2 in promoting global histone acetylation, beside its role in promoting local histone acetylation at SOX2 binding regions. Combined metabolic and transcriptional analyses revealed two mechanisms by which SOX2 drives up global histone acetylation in ESCCs: promoting the expression of a panel of histone acetyltransferases and reducing long chain fatty acid synthesis/elongation at least in part by repressing the expression of long-chain acyl-CoA synthase 5 (ACSL5), which in turn channels acetyl-CoA to histone acetylation. We demonstrated that ACSL5 knockdown downregulated fatty acid synthesis/elongation and enhanced histone acetylation, whereas overexpression of ACSL5 resulted in lipid accumulation, histone hypoacetylation, and tumor growth inhibition. Finally, we showed that SOX2 expression correlates negatively with ACSL5 and positively with histone acetylation in clinical esophageal squamous tumors. Altogether, our study uncovers a role of SOX2 in reprogramming lipid metabolism and driving histone hyperacetylation and super-enhancer function, providing new mechanistic insights of SOX2 acting as a potent oncodriver.
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Project description:SOX2 is not only a pioneer transcription factor with critical roles in stem cell function and cell reprogramming but also a potent initiating oncodriver for a multitude of squamous cancers. How SOX2 exerts a potent oncogenic activity in squamous lineage is largely unknown. Here we uncovered a unique role of SOX2 in driving global histone acetylation and demonstrated that SOX2 is required for the formation of about half of the super-enhancers in esophageal squamous cancer cells (ESCCs). Combined metabolic, chromatin and transcriptional analysis revealed at least two mechanisms by which SOX2 drives histone acetylation in ESCCs: promoting the expression of a panel of histone acetyltransferases and program fatty acid metabolism, which channels acetyl-CoA to histone acetylation by promoting the expression of multiple genes in fatty acid -oxidation and by repressing the expression of long-chain acyl-CoA synthase 5 (ACSL5) involved in fatty acid synthesis. We demonstrated that ACSL5 knockdown downregulated fatty acid synthesis and enhanced histone acetylation, whereas overexpression of ACSL5 resulted in lipid accumulation, histone hypoacetylation, and tumor growth inhibition. Finally, we showed that SOX2 expression correlates negatively with ACSL5 and positively with histone acetylation in clinical esophageal squamous tumors. Altogether, our study uncovers a role of SOX2 in reprogramming lipid metabolism and driving histone hyperacetylation and super-enhancer function, providing new mechanistic insights of SOX2 acting as a potent oncodriver.
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Project description:SOX2 is not only a pioneer transcription factor with critical roles in stem cell function and cell reprogramming but also a potent initiating oncodriver for a multitude of squamous cancers. How SOX2 exerts a potent oncogenic activity in squamous lineage is largely unknown. Here we uncovered a unique role of SOX2 in driving global histone acetylation and demonstrated that SOX2 is required for the formation of about half of the super-enhancers in esophageal squamous cancer cells (ESCCs). Combined metabolic, chromatin and transcriptional analysis revealed at least two mechanisms by which SOX2 drives histone acetylation in ESCCs: promoting the expression of a panel of histone acetyltransferases and program fatty acid metabolism, which channels acetyl-CoA to histone acetylation by promoting the expression of multiple genes in fatty acid -oxidation and by repressing the expression of long-chain acyl-CoA synthase 5 (ACSL5) involved in fatty acid synthesis. We demonstrated that ACSL5 knockdown downregulated fatty acid synthesis and enhanced histone acetylation, whereas overexpression of ACSL5 resulted in lipid accumulation, histone hypoacetylation, and tumor growth inhibition. Finally, we showed that SOX2 expression correlates negatively with ACSL5 and positively with histone acetylation in clinical esophageal squamous tumors. Altogether, our study uncovers a role of SOX2 in reprogramming lipid metabolism and driving histone hyperacetylation and super-enhancer function, providing new mechanistic insights of SOX2 acting as a potent oncodriver.
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Project description:Differences in global levels of histone acetylation occur in normal and cancer cells, although the reason cells regulate these levels has remained unclear. Here we demonstrate a role for histone acetylation in regulating intracellular pH (pHi). As pHi decreases, histones are globally deacetylated by histone deacetylases (HDACs) and the released acetate anions are co-exported with protons out of the cell by monocarboxylate transporters (MCTs), preventing further reductions in pHi. Conversely, global histone acetylation increases at more alkaline pHi, such as when resting cells are induced to proliferate. Inhibition of HDACs or MCTs decreases acetate export and lowers pHi, particularly compromising pHi maintenance in acidic environments. Global deacetylation at low pH is reflected at a genomic level by decreased abundance and extensive redistribution of acetylation at promoters and intergenic regions. Thus acetylation of chromatin functions as a rheostat to regulate pHi with important implications for therapeutic use of HDAC inhibitors. To investigate the redistribution of H4K16ac throughout the genome upon treatment at pH 6.5
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Project description:Regulation of histone acetylation is fundamental to the utilisation of eukaryotic genomes in chromatin. Aberrant acetylation contributes to disease and can be clinically combated by inhibiting the responsible enzymes. Our knowledge of the histone acetylation system is patchy because we so far lacked the methodology to describe acetylation patterns and their genesis by integrated enzyme activities. We devised a generally applicable, mass spectrometry-based strategy to precisely and accurately quantify combinatorial modification motifs. This was applied to generate a comprehensive inventory of acetylation motifs on histones H3 and H4 in Drosophila cells. Systematic depletion of known or suspected acetyltransferases and deacetylases revealed specific alterations of histone acetylation signatures, established enzyme-substrate relationships and unveiled an extensive crosstalk between neighboring modifications. Unexpectedly, overall histone acetylation levels remained remarkably constant upon depletion of individual acetyltransferases. Conceivably, the acetylation level is adjusted to maintain the global charge neutralisation of chromatin and the stability of nuclei.
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