A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α

Abstract

Emerging evidence points to aberrant regulation of translation as a driver of cell transformation in cancer. Given the direct control of translation by tRNA modifications, tRNA modifying enzymes may function as regulators of cancer progression. Here, we show that a tRNA methyltransferase 9-like (hTRM9L/KIAA1456) mRNA is down-regulated in breast, bladder, colorectal, cervix and testicular carcinomas. In the aggressive SW620 and HCT116 colon carcinoma cell lines, hTRM9L is silenced and its re-expression and methyltransferase activity dramatically suppressed tumour growth in vivo. This growth inhibition was linked to decreased proliferation, senescence-like G0/G1-arrest and up-regulation of the RB interacting protein LIN9. Additionally, SW620 cells re-expressing hTRM9L did not respond to hypoxia via HIF1-α-dependent induction of GLUT1. Importantly, hTRM9L-negative tumours were highly sensitive to aminoglycoside antibiotics and this was associated with altered tRNA modification levels compared to antibiotic resistant hTRM9L-expressing SW620 cells. Our study links hTRM9L and tRNA modifications to inhibition of tumour growth via LIN9 and HIF1-α-dependent mechanisms. It also suggests that aminoglycoside antibiotics may be useful to treat hTRM9L-deficient tumours.

DOI: 10.1002/emmm.201201161

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@inproceedings{Begley2013AHT, title={A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α}, author={Ulrike Begley and Mar{\'i}a Soledad Sosa and Alvaro Avivar-Valderas and Ashish Patil and Lauren Endres and Yeriel D Estrada and Clement TY Chan and Dan Su and Peter C . Dedon and Julio A. Aguirre-Ghiso and Thomas J. Begley}, booktitle={EMBO molecular medicine}, year={2013} }