Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma

作者：Yu Tian, Haijuan Xiao, Yanhui Yang, Pingping Zhang, J. Yuan, Wei Zhang, Lijie Chen, Yibao Fan, Jinze Zhang, Huan Cheng, Tingwei Deng, Lin Yang, Weiwei Wang, Guoyong Chen, Peiqin Wang, Peng Gong, Xing Niu, Xianbin Zhang · 发表于：Molecular Cancer · 年份：2023 · DOI：10.1186/s12943-022-01706-6 · 被引用次数：108 · 研究领域：Epigenetics and DNA Methylation、Ferroptosis and cancer prognosis、Immune cells in cancer

Abstract Background Accumulated evidence highlights the significance of the crosstalk between epigenetic and epitranscriptomic mechanisms, notably 5-methylcytosine (5mC) and N 6 -methyladenosine (m 6 A). Herein, we conducted a widespread analysis regarding the crosstalk between 5mC and m 6 A regulators in hepatocellular carcinoma (HCC). Methods Pan-cancer genomic analysis of the crosstalk between 5mC and m 6 A regulators was presented at transcriptomic, genomic, epigenetic, and other multi-omics levels. Hub 5mC and m 6 A regulators were summarized to define an epigenetic and epitranscriptomic module eigengene (EME), which reflected both the pre- and post-transcriptional modifications. Results 5mC and m 6 A regulators interacted with one another at the multi-omic levels across pan-cancer, including HCC. The EME scoring system enabled to greatly optimize risk stratification and accurately predict HCC patients’ clinical outcomes and progression. Additionally, the EME accurately predicted the responses to mainstream therapies (TACE and sorafenib) and immunotherapy as well as hyper-progression. In vitro, 5mC and m 6 A regulators cooperatively weakened apoptosis and facilitated proliferation, DNA damage repair, G2/M arrest, migration, invasion and epithelial-to-mesenchymal transition (EMT) in HCC cells. The EME scoring system was remarkably linked to potential extrinsic and intrinsic immune escape mechanisms, and the high EME might contribute to a reduced copy number gain/loss freq...