Open AccessA human tRNA methyltransferase 9‐like protein prevents tumour growth by regulating LIN9 and HIF1‐α
Author(s) -
Begley Ulrike,
Sosa Maria Soledad,
AvivarValderas Alvaro,
Patil Ashish,
Endres Lauren,
Estrada Yeriel,
Chan Clement T.Y.,
Su Dan,
Dedon Peter C.,
AguirreGhiso Julio A.,
Begley Thomas
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201201161
Subject(s) - methyltransferase , transfer rna , microbiology and biotechnology , biochemistry , protein biosynthesis , chemistry , biology , cancer research , rna , dna , methylation , gene
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.