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The tRNA Gm18 methyltransferase TARBP1 promotes hepatocellular carcinoma progression via metabolic reprogramming of glutamine

Abstract

Cancer cells rely on metabolic reprogramming to sustain the prodigious energetic requirements for rapid growth and proliferation. Glutamine metabolism is frequently dysregulated in cancers and is being exploited as a potential therapeutic target. Using CRISPR/Cas9 interference (CRISPRi) screening, we identified TARBP1 (TAR (HIV-1) RNA Binding Protein 1) as a critical regulator involved in glutamine reliance of cancer cell. Consistent with this discovery, TARBP1 amplification and overexpression are frequently observed in various cancers. Knockout of TARBP1 significantly suppresses cell proliferation, colony formation and xenograft tumor growth. Mechanistically, TARBP1 selectively methylates and stabilizes a small subset of tRNAs, which promotes efficient protein synthesis of glutamine transporter-ASCT2 (also known as SLC1A5) and glutamine import to fuel the growth of cancer cell. Moreover, we found that the gene expression of TARBP1 and ASCT2 are upregulated in combination in clinical cohorts and their upregulation is associated with unfavorable prognosis of HCC (hepatocellular carcinoma). Taken together, this study reveals the unexpected role of TARBP1 in coordinating the tRNA availability and glutamine uptake during HCC progression and provides a potential target for tumor therapy.

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Fig. 1: CRISPRi/Cas9 library screening identified TARBP1 as a novel regulator of cancer glutamine metabolism.
Fig. 2: TARBP1 is necessary for tumor growth.
Fig. 3: TARBP1 is the Gm18 methyltransferase targeting tRNAGln-TTG/CTG and tRNASer-TGA/GCT.
Fig. 4: TARBP1 affects mRNA translation possibly by regulating the stability of Gm18-modified tRNAs.
Fig. 5: TARBP1 enhances glutamine metabolism via translation regulation of ASCT2.
Fig. 6: The expression of TARBP1 and ASCT2 is correlated and associated with HCC patient prognosis.

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Data availability

The raw data of this study is available in the GEO database under the accession number: GSE236369.

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Acknowledgements

We would like to thank all members in Hao Chen’s Lab for their help and advice in experimental design. We thank Prof. Ruilin Tian for sharing the CRISPRi/Cas9 library screening vectors and all kind suggestions. The authors would also like to acknowledge the technical support from Hua Li and Lin Lin at SUSTech CRFT. This work was supported by Center for Computational Science and Engineering at Southern University of Science and Technology.

Funding

This work was supported by National Key Research and Development Program of China (2022YFC2702705), National Natural Science Foundation of China (31971330 and 32170586 to HHM, 82272703 to JBC, 32170604 to HC) and the Lingang Laboratory (Grant No.LG-QS-202204-04 to JBC). This work was also supported by Shenzhen Science and Technology Program (20231120115406001 and JCYJ20230807153703008), Pearl River Recruitment Program of Talents (2021QN02Y122) and Department of Health of Guangdong Province (B2021032) to HC, Shenzhen Key Laboratory of Gene Regulation and Systems Biology (Grant No. ZDSYS20200811144002008) from Shenzhen Innovation Committee of Science and Technology and Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (ZYCXTD2023004).

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HHM and HC designed and conceived the experiments. YYZ and XYS performed most of the experiments. JBC provided clinical samples. JW and LYW performed pathological analysis. RQW and YLC assisted in CRISPRi/Cas9 library screening. YG helped to prepare figures. MGX and NJO assisted in polysome profiling. YCW, QL, and HC analyzed the data. XYS and HC wrote the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Qi Liu, Honghui Ma, Jiabin Cai or Hao Chen.

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The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Zhongshan Hospital Research Ethics Committee, and written informed consent was obtained from each patient. Animal experiments were approved by the Institutional Animal Care and Use Committees (IACUC) of SUSTech.

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Shi, X., Zhang, Y., Wang, Y. et al. The tRNA Gm18 methyltransferase TARBP1 promotes hepatocellular carcinoma progression via metabolic reprogramming of glutamine. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01323-4

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