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.