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

EMBO Mol Med. 2013 Mar;5(3):366-83. doi: 10.1002/emmm.201201161. Epub 2013 Feb 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Hypoxia
  • Cell Proliferation
  • Chick Embryo
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy*
  • Down-Regulation
  • Epigenesis, Genetic
  • G1 Phase Cell Cycle Checkpoints
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Genetic Therapy*
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • Mice, Nude
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Paromomycin / pharmacology
  • RNA, Messenger / metabolism
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Time Factors
  • Transfection
  • Tumor Burden
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Xenograft Model Antitumor Assays
  • tRNA Methyltransferases / genetics
  • tRNA Methyltransferases / metabolism*

Substances

  • Antibiotics, Antineoplastic
  • Glucose Transporter Type 1
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • LIN9 protein, human
  • Nuclear Proteins
  • RNA, Messenger
  • SLC2A1 protein, human
  • Saccharomyces cerevisiae Proteins
  • Tumor Suppressor Proteins
  • Paromomycin
  • TRM9 protein, S cerevisiae
  • TRMT9B protein, human
  • tRNA Methyltransferases