Crosstalk between 5-methylcytosine and N-6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma
机构：[1]Department of General Surgery and Integrated Chinese and WesternMedicine, Institute of Precision Diagnosis and Treatment of Digestive SystemTumors, Carson International Cancer Center, Shenzhen University GeneralHospital, Shenzhen University, Shenzhen, Guangdong 518055, China深圳市康宁医院深圳医学信息中心[2]Department of Oncology, Shaanxi Province, Affiliated Hospital of the ShaanxiUniversity of Traditional Chinese Medicine, Xianyang, Shaanxi 712046, China[3]Department of Trauma Surgery, The First Affiliated Hospital and Collegeof Clinical Medicine, Henan University of Science and Technology, Luoyang471003, Henan, China[4]Department of Gastroenterology, ChanghaiHospital, Naval Medical University, Shanghai 200433, China[5]China MedicalUniversity, Shenyang 110122, Liaoning, China[6]Department of HepatobiliarySurgery, Shaanxi Province, Xianyang Central Hospital, Xianyang 712099, Shaanxi, China[7]Hepatobiliary Surgery, People’s Hospital of ZhengzhouUniversity and Henan Provincial People’s Hospital, Zhengzhou 450001, Henan,China[8]Department of Gastroenterology, Changzheng Hospital, Naval MedicalUniversity, Shanghai 200003, China
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 multiomic 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 frequency. Finally, we determined potential therapeutic compounds and druggable targets (TUBB1 and P2RY4) for HCC patients with high EME.Conclusions Our findings suggest that HCC may result from a unique synergistic combination of 5mC-epigenetic mechanism mixed with m(6)A-epitranscriptomic mechanism, and their crosstalk defines therapeutic response and pharmacogenomic landscape.
第一作者机构：[1]Department of General Surgery and Integrated Chinese and WesternMedicine, Institute of Precision Diagnosis and Treatment of Digestive SystemTumors, Carson International Cancer Center, Shenzhen University GeneralHospital, Shenzhen University, Shenzhen, Guangdong 518055, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of General Surgery and Integrated Chinese and WesternMedicine, Institute of Precision Diagnosis and Treatment of Digestive SystemTumors, Carson International Cancer Center, Shenzhen University GeneralHospital, Shenzhen University, Shenzhen, Guangdong 518055, China[5]China MedicalUniversity, Shenyang 110122, Liaoning, China[7]Hepatobiliary Surgery, People’s Hospital of ZhengzhouUniversity and Henan Provincial People’s Hospital, Zhengzhou 450001, Henan,China
推荐引用方式(GB/T 7714)：
Tian Yu,Xiao Haijuan,Yang Yanhui,et al.Crosstalk between 5-methylcytosine and N-6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma[J].MOLECULAR CANCER.2023,22(1):doi:10.1186/s12943-022-01706-6.
APA：
Tian, Yu,Xiao, Haijuan,Yang, Yanhui,Zhang, Pingping,Yuan, Jiahui...&Zhang, Xianbin.(2023).Crosstalk between 5-methylcytosine and N-6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma.MOLECULAR CANCER,22,(1)
MLA：
Tian, Yu,et al."Crosstalk between 5-methylcytosine and N-6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma".MOLECULAR CANCER 22..1(2023)
医学