Genetic and Molecular Characterization Revealed the Prognosis Efficiency of Histone Acetylation in Pan-Digestive Cancers

Abstract

The imbalance between acetylation and deacetylation of histone proteins, important for epigenetic modifications, is closely associated with various diseases, including cancer. However, knowledge regarding the modification of histones across the different types of digestive cancers is still lacking. The purpose of this research was to analyze the role of histone acetylation and deacetylation in pan-digestive cancers. We systematically characterized the molecular alterations and clinical relevance of 13 histone acetyltransferase (HAT) and 18 histone deacetylase (HDAC) genes in five types of digestive cancers, including esophageal carcinoma, gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. Recurrent mutations and copy number variation (CNV) were extensively found in acetylation-associated genes across pan-digestive cancers. HDAC9 and KAT6A showed widespread copy number amplification across five pan-digestive cancers, while ESCO2, EP300, and HDAC10 had prevalent copy number deletions. Accordingly, we found that HAT and HDAC genes correlated with multiple cancer hallmark-related pathways, especially the histone modification-related pathway, PRC2 complex pathway. Furthermore, the expression pattern of HAT and HDAC genes stratified patients with clinical benefit in hepatocellular carcinoma and pancreatic cancer. These results indicated that acetylation acts as a key molecular regulation of pan-digestive tumor progression.

Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth

“…Interestingly, Kaplan-Meier curves available at the Human Protein Atlas (proteinatlas.org) (40) demonstrate that cancers in which high HDAC10 expression is associated with poor prognosis include those that are associated with TMEs enriched in excretory products, including renal cancer and colon adenocarcinoma. A recent analysis of TCGA data reported HDAC10 copy number gains as a risk factor for colorectal and pancreatic cancers (41). A study of colon cancer patients in China reported constitutively elevated expression of HDAC10 protein in tumor tissues compared to paired adjacent tissue in the majority of patients J o u r n a l P r e -p r o o f (9), with the greatest difference observed in cytoplasmic HDAC10.…”

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

“…Inhibition of Plk1 phosphorylation and its downstream target HBO1 reverse the onset of resistance. However, abnormal expressions of several other histone‐modifying enzymes were also identified 259 . The high transcriptional levels of HDAC7 and HDAC2 are involved in the progression of pancreatic cancer 260 .…”

Epigenetic modifications in esophageal cancer: An evolving biomarker

“…The obtained results revealed that low expression of H3K18Ac and H3K27triMe was associated with better prognosis in patients with ESCC, especially in early-stage patients ( Tzao et al, 2009 ). In addition, Zhang et al (2022) investigated five digestive cancers, including esophageal, gastric, hepatocellular, pancreatic and colorectal cancers, by systematically examining 13 HAT and 18 HDAC genes. As a result, histone acetylation was found to be a key regulatory molecule in digestive cancer.…”