Journal
EMBO MOLECULAR MEDICINE
Volume 5, Issue 3, Pages 366-383Publisher
WILEY-BLACKWELL
DOI: 10.1002/emmm.201201161
Keywords
cancer; hTRM9L; hypoxia; translation; tRNA modification
Categories
Funding
- National Institute of Environmental Health Sciences [R01 ES015037, R01 ES017010, R21 ES017146, P30 ES002109]
- National Cancer Institute [R01 CA109182, U54 CA163131]
- National Science Foundation [NSF 0922830]
- NYSTAR
- MIT Westaway Fund
- Singapore-MIT Alliance for Research and Technology
- Samuel Waxman Cancer Research Foundation Tumour Dormancy Program
- NYSTEM
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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--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--dependent mechanisms. It also suggests that aminoglycoside antibiotics may be useful to treat hTRM9L-deficient tumours.
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