A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α
Article first published online: 4 FEB 2013
Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 3, pages 366–383, March 2013
How to Cite
Begley, U., Sosa, M. S., Avivar-Valderas, A., Patil, A., Endres, L., Estrada, Y., Chan, C. T.Y., Su, D., Dedon, P. C., Aguirre-Ghiso, J. A. and Begley, T. (2013), A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α. EMBO Mol Med, 5: 366–383. doi: 10.1002/emmm.201201161
- Issue published online: 5 MAR 2013
- Article first published online: 4 FEB 2013
- Manuscript Accepted: 7 DEC 2012
- Manuscript Revised: 5 DEC 2012
- Manuscript Received: 15 DEC 2011
- National Institute of Environmental Health Sciences
- Funded Access
- tRNA modification
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.