2. Academic Validation
  3. N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism

N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism

  • Nat Commun. 2021 Nov 2;12(1):6314. doi: 10.1038/s41467-021-26718-6.
Yanying Wang # 1,  Jing Wang # 2,  Xiaoyu Li # 3,  Xushen Xiong # 3,  Jianyi Wang 2,  Ziheng Zhou 2,  Xiaoxiao Zhu 4,  Yang Gu 2 5,  Dan Dominissini 6,  Lei He 7,  Yong Tian 8 9,  Chengqi Yi 10,  Zusen Fan 11 12
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. wangyanying@moon.ibp.ac.cn.
  • 2 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
  • 3 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
  • 4 CAS Key Laboratory of RNA Biology; Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
  • 5 University of Chinese Academy of Sciences, 100049, Beijing, China.
  • 6 Cancer Research Center and Wohl Institute for Translational Medicine, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel.
  • 7 Department of Hepatobiliary Surgery, PLA General Hospital, 100853, Beijing, China.
  • 8 CAS Key Laboratory of RNA Biology; Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. ytian@ibp.ac.cn.
  • 9 University of Chinese Academy of Sciences, 100049, Beijing, China. ytian@ibp.ac.cn.
  • 10 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. chengqi.yi@pku.edu.cn.
  • 11 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. fanz@moon.ibp.ac.cn.
  • 12 University of Chinese Academy of Sciences, 100049, Beijing, China. fanz@moon.ibp.ac.cn.
  • # Contributed equally.
PMID: 34728628 DOI: 10.1038/s41467-021-26718-6
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 N1-methyladenosine methylation (m1A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m1A methylation signals are increased in liver Cancer Stem Cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m1A methylation in a subset of tRNA to increase PPARδ 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.

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