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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2024

Open Access 01-12-2024 | Hepatocellular Carcinoma | Research

METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation

Authors: Meilin Xue, Lei Dong, Honghai Zhang, Yangchan Li, Kangqiang Qiu, Zhicong Zhao, Min Gao, Li Han, Anthony K. N. Chan, Wei Li, Keith Leung, Kitty Wang, Sheela Pangeni Pokharel, Ying Qing, Wei Liu, Xueer Wang, Lili Ren, Hongjie Bi, Lu Yang, Chao Shen, Zhenhua Chen, Laleh Melstrom, Hongzhi Li, Nikolai Timchenko, Xiaolan Deng, Wendong Huang, Steven T. Rosen, Jingyan Tian, Lin Xu, Jiajie Diao, Chun-Wei Chen, Jianjun Chen, Baiyong Shen, Hao Chen, Rui Su

Published in: Journal of Hematology & Oncology | Issue 1/2024

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Abstract

Background

While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying liver CSC self-renewal remains elusive. We aim to characterize the role of Methyltransferase 16 (METTL16), a recently identified RNA N6-methyladenosine (m6A) methyltransferase, in HCC development/maintenance, CSC stemness, as well as normal hepatogenesis.

Methods

Liver-specific Mettl16 conditional KO (cKO) mice were generated to assess its role in HCC pathogenesis and normal hepatogenesis. Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis and xenograft models were utilized to determine the role of METTL16 in HCC initiation and progression. A limiting dilution assay was utilized to evaluate CSC frequency. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq, RNA immunoprecipitation (RIP)-seq, and ribosome profiling.

Results

METTL16 is highly expressed in liver CSCs and its depletion dramatically decreased CSC frequency in vitro and in vivo. Mettl16 KO significantly attenuated HCC initiation and progression, yet only slightly influenced normal hepatogenesis. Mechanistic studies, including high-throughput sequencing, unveiled METTL16 as a key regulator of ribosomal RNA (rRNA) maturation and mRNA translation and identified eukaryotic translation initiation factor 3 subunit a (eIF3a) transcript as a bona-fide target of METTL16 in HCC. In addition, the functionally essential regions of METTL16 were revealed by CRISPR gene tiling scan, which will pave the way for the development of potential inhibitor(s).

Conclusions

Our findings highlight the crucial oncogenic role of METTL16 in promoting HCC pathogenesis and enhancing liver CSC self-renewal through augmenting mRNA translation efficiency.
Appendix
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Metadata
Title
METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation
Authors
Meilin Xue
Lei Dong
Honghai Zhang
Yangchan Li
Kangqiang Qiu
Zhicong Zhao
Min Gao
Li Han
Anthony K. N. Chan
Wei Li
Keith Leung
Kitty Wang
Sheela Pangeni Pokharel
Ying Qing
Wei Liu
Xueer Wang
Lili Ren
Hongjie Bi
Lu Yang
Chao Shen
Zhenhua Chen
Laleh Melstrom
Hongzhi Li
Nikolai Timchenko
Xiaolan Deng
Wendong Huang
Steven T. Rosen
Jingyan Tian
Lin Xu
Jiajie Diao
Chun-Wei Chen
Jianjun Chen
Baiyong Shen
Hao Chen
Rui Su
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2024
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-024-01526-9

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