| Title | N-1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism |
| Authors | Wang, Yanying Wang, Jing Li, Xiaoyu Xiong, Xushen Wang, Jianyi Zhou, Ziheng Zhu, Xiaoxiao Gu, Yang Dominissini, Dan He, Lei Tian, Yong Yi, Chengqi Fan, Zusen |
| Affiliation | Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Inst Biophys, CAS Key Lab Infect & Immun, Beijing 100101, Peoples R China Peking Univ, Peking Tsinghua Ctr Life Sci, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Beijing, Peoples R China Chinese Acad Sci, CAS Key Lab RNA Biol, Beijing 100101, Peoples R China Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China Univ Chinese Acad Sci, Beijing 100049, Peoples R China Tel Aviv Univ, Sackler Fac Med, Chaim Sheba Med Ctr, Canc Res Ctr, IL-6997801 Tel Aviv, Israel Tel Aviv Univ, Sackler Fac Med, Chaim Sheba Med Ctr, Wohl Inst Translat Med, IL-6997801 Tel Aviv, Israel Peoples Liberat Army Gen Hosp, Dept Hepatobiliary Surg, Beijing 100853, Peoples R China |
| Keywords | GENOME-WIDE ANALYSIS M(1)A58 METHYLTRANSFERASE IN-VIVO CANCER TRANSLATION STEMNESS HEDGEHOG 1-METHYLADENOSINE METHYLOME COMPLEX |
| Issue Date | 2-Nov-2021 |
| Publisher | NATURE COMMUNICATIONS |
| Abstract | Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N-1-methyladenosine methylation (m(1)A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m(1)A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m(1)A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m(1)A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m(1)A methylation in a subset of tRNA to increase PPAR delta translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer. Metabolic adaptation has been reported to promote cancer, yet the underlying mechanisms are not clear. Here, the authors show that m(1)A methylation in tRNA regulates cholesterol metabolism in liver cancer stem cells and m(1)A inhibition decreases tumourigenesis in preclinical models of hepatocellular carcinoma. |
| URI | http://hdl.handle.net/20.500.11897/629070 |
| DOI | 10.1038/s41467-021-26718-6 |
| Indexed | SCI(E) |
| Appears in Collections: | 生命科学学院 |
