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

Ulrike Begley, Maria Soledad Sosa, Alvaro Avivar-Valderas, Ashish Patil, Lauren Endres, Yeriel Estrada, Clement T.Y. Chan, Dan Su, Peter C. Dedon, Julio A. Aguirre-Ghiso, Thomas Begley

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

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. The human tRNA methyltransferase 9-like (hTRM9L) gene is turned off in many cancers and hTRM9- deficient cells are susceptible to killing by aminoglycoside antibiotics, suggesting that these drugs could be re-purposed to treat late stage cancers.

Original languageEnglish (US)
Pages (from-to)366-383
Number of pages18
JournalEMBO Molecular Medicine
Volume5
Issue number3
DOIs
StatePublished - Mar 2013
Externally publishedYes

Keywords

  • Cancer
  • HTRM9L
  • Hypoxia
  • Translation
  • TRNA modification

ASJC Scopus subject areas

  • Molecular Medicine

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