Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong & Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine; Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, 518055, China.
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Institutes of Biomedical Sciences, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, 200032, China.
Cell Death Differ. 2024 Sep;31(9):1219-1234. doi: 10.1038/s41418-024-01323-4. Epub 2024 Jun 12.
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.
癌细胞依赖于代谢重编程来维持其快速生长和增殖所需要的巨大能量。谷氨酰胺代谢在癌症中经常失调，并且正被作为一个潜在的治疗靶点进行研究。通过使用 CRISPR/Cas9 干扰（CRISPRi）筛选，我们发现 TARBP1（HIV-1 的 TAR RNA 结合蛋白 1）是一个参与癌细胞对谷氨酰胺依赖的关键调节因子。与这一发现一致的是，TARBP1 扩增和过表达经常在各种癌症中观察到。TARBP1 的敲除显著抑制了细胞增殖、集落形成和异种移植肿瘤的生长。在机制上，TARBP1 选择性地上甲基化和稳定一小部分 tRNA，促进了谷氨酰胺转运体 ASCT2（也称为 SLC1A5）的高效蛋白质合成和谷氨酰胺的摄取，为癌细胞的生长提供燃料。此外，我们发现 TARBP1 和 ASCT2 的基因表达在临床队列中联合上调，并且它们的上调与 HCC（肝细胞癌）的不良预后相关。综上所述，这项研究揭示了 TARBP1 在协调 HCC 进展过程中 tRNA 可用性和谷氨酰胺摄取方面的意外作用，并为肿瘤治疗提供了一个潜在的靶点。
