title: A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α.
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.
authors: College of Nanoscale Science and Engineering, University at Albany, State University of New York, Albany, NY, USA.
authors: Ulrike
authors: U
authors: Begley
authors: Maria Soledad
authors: MS
authors: Sosa
authors: Alvaro
authors: A
authors: Avivar-Valderas
authors: Ashish
authors: A
authors: Patil
authors: Lauren
authors: L
authors: Endres
authors: Yeriel
authors: Y
authors: Estrada
authors: Clement T Y
authors: CT
authors: Chan
authors: Dan
authors: D
authors: Su
authors: Peter C
authors: PC
authors: Dedon
authors: Julio A
authors: JA
authors: Aguirre-Ghiso
authors: Thomas
authors: T
authors: Begley
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002642:Chick Embryo; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D059585:G1 Phase Cell Cycle Checkpoints; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010303:Paromomycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D012359:tRNA Methyltransferases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C501563:LIN9 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; C495677:SLC2A1 protein, human; D029701:Saccharomyces cerevisiae Proteins; D025521:Tumor Suppressor Proteins; D010303:Paromomycin; C480488:TRM9 protein, S cerevisiae; C582289:TRMT9B protein, human; D012359:tRNA Methyltransferases
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