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A Human Trna Methyltransferase 9Like Protein Prevents Tumour

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A Human Trna Methyltransferase 9Like Protein Prevents Tumour A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-# The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Begley, Ulrike, Maria Soledad Sosa, Alvaro Avivar-Valderas, Ashish Patil, Lauren Endres, Yeriel Estrada, Clement T.Y. Chan, et al. “A Human tRNA Methyltransferase 9-Like Protein Prevents Tumour Growth by Regulating LIN9 and HIF1-α.” EMBO Molecular Medicine 5, no. 3 (March 2013): 366–383. As Published http://dx.doi.org/10.1002/emmm.201201161 Publisher Wiley Blackwell Version Final published version Citable link http://hdl.handle.net/1721.1/88185 Terms of Use Creative Commons Attribution 3.0 Detailed Terms http://creativecommons.org/licenses/by/3.0/ OPEN TRANSPARENT Research Article ACCESS PROCESS hTRM9L suppresses tumour growth A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-a Ulrike Begley3, Maria Soledad Sosa1, Alvaro Avivar-Valderas1, Ashish Patil4, Lauren Endres3, Yeriel Estrada1, Clement T.Y. Chan5, Dan Su6, Peter C. Dedon6,7, Julio A. Aguirre-Ghiso1,2*, Thomas Begley3* Keywords: cancer; hTRM9L; hypoxia; Emerging evidence points to aberrant regulation of translation as a driver of translation; tRNA modification 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/ DOI 10.1002/emmm.201201161 KIAA1456) mRNA is down-regulated in breast, bladder, colorectal, cervix and Received December 15, 2011 testicular carcinomas. In the aggressive SW620 and HCT116 colon carcinoma cell Revised December 05, 2012 lines, hTRM9L is silenced and its re-expression and methyltransferase activity Accepted December 07, 2012 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-a-dependent induction of GLUT1. Importantly, hTRM9L-negative tumours were highly sensitive to aminoglycoside antibiotics and this was associated with altered tRNA modification levels com- pared to antibiotic resistant hTRM9L-expressing SW620 cells. Our study links hTRM9L and tRNA modifications to inhibition of tumour growth via LIN9 and HIF1-a-dependent mechanisms. It also suggests that aminoglycoside antibiotics may be useful to treat hTRM9L-deficient tumours. (1) Division of Hematology and Oncology, Department of Medicine, Department INTRODUCTION of Otolaryngology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY The regulation of translation has primarily been studied at (2) Black Family Stem Cell Institute, Mount Sinai School of Medicine, New the level of initiation, with both CAP-dependent and CAP- York, NY independent regulatory mechanisms playing vital roles in (3) College of Nanoscale Science and Engineering, University at Albany, State cellular proliferation, stress signalling and cell cycle progression University of New York, Albany, NY (Komar & Hatzoglou, 2011; Sonenberg & Hinnebusch, 2009; (4) Department of Biomedical Sciences, School of Public Health, University at Albany, State University of New York, Albany, NY Sonenberg et al, 2000). Translation elongation is another (5) Department of Chemistry, Massachusetts Institute of Technology, regulatory strategy and, at its core, requires the efficient Cambridge, MA interaction of codons and anticodons found on mRNA and (6) Department of Biological Engineering, Massachusetts Institute of tRNA, respectively. Enzyme catalysed modification of tRNA has Technology, Cambridge, MA been shown to dramatically affect codon–anticodon interactions (7) Center for Environmental Health Sciences, Massachusetts Institute of (Murphy et al, 2004; Yarian et al, 2002). Among the tRNA Technology, Cambridge, MA modifications in eukaryotes, wobble uridine modifications have *Corresponding author: Tel: þ1 518 956-7301; Fax: þ 1 518 437 8687; E-mail: [email protected] been well studied in Saccharomyces cerevisiae, with 11 of 13 5 *Corresponding author: Tel: þ1 212 241 9582; Fax: þ1 212 241 4096; tRNAs possessing either 5-carbamoylmethyluridine (ncm U), E-mail: [email protected] the 20-O-ribose-methylated form ncm5Um, 5-methoxycarbonyl- ß 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any 366 medium, provided the original work is properly cited. EMBO Mol Med (2013) 5, 366–383 www.embomolmed.org Research Article Ulrike Begley et al. methyluridine (mcm5U) or 5-methoxycarbonylmethyl-2-thio- other genes are located, decreased the colony formation of uridine (mcm5s2U; Johansson et al, 2008). Wobble uridine and specific colorectal cancer lines. anticodon-associated modifications on tRNA molecules pro- Wobble base modifications catalysed by yeast Trm9 and mote or restrict specific anticodon–codon interactions and can ALKBH8 proteins play important roles in stress signalling influence translation speed and fidelity. In fact, the levels of pathways, with responses to DNA damage and reactive oxygen many modifications associated with the structure of the species as prime examples (Begley et al, 2007; Chan et al, 2010; anticodon (positions 34 or 37) change in response to cellular Fu et al, 2010a; Songe-Moller et al, 2010). The potential presence stress, supporting that translation elongation is dynamically of a tumour suppressor on chromosome 8, in a region that regulated (Chan et al, 2010). encodes hTRM9L, and the linkage between tumour suppressors The completion of the wobble uridine modification mcm5U and stress signalling pathways led us to postulate that hTRM9L (a precursor for mcm5s2U) is catalysed by yeast tRNA methyl- could play a role in controlling tumour growth. In this study, we transferase 9 (Trm9) and its mammalian homolog ALKBH8 show that hTRM9L is a powerful negative regulator of tumour (Begley et al, 2007; Fu et al, 2010a; Songe-Moller et al, 2010). growth and that the hTRM9L transcript is significantly down- Amino acid sequence analyses reveal one gene encoding Trm9 regulated in breast, bladder, cervix, testicular and colorectal in S. cerevisiae (Trm9) and two Trm9 homologs in mammals carcinomas. Further, we demonstrate that the down-regulation (KIAA1456 and ALKBH8; Fig 1A). Trm9 has been biochemically of hTRM9L is due to epigenetic silencing in advanced colorectal characterized. After elongator complex proteins generate the cancer cell lines. Importantly, re-expression of hTRM9L strongly substrate cm5U, Trm9 uses the methyl donor S-adenosyl inhibits SW620 and HCT116 colon carcinoma cell tumouri- methionine (SAM) to complete the formation of mcm5-based genicity in vivo via a senescence-like G0/G1-arrest. Further, we modifications. Trm9 forms a complex with Trm112 to catalyse show that inhibition of tumour growth by hTRM9L is dependent the last step in the formation of mcm5U (Mazauric et al, 2010). on a functional SAM binding domain. Tumour growth inhibition Clarke and coworkers initially characterized Trm9 and demon- by hTRM9L is linked to increased transcription of the RB strated that it modifies wobble uridines in specific arginine and interacting protein LIN9 and to a failure of hTRM9L-expressing glutamic acid tRNAs. They further showed that Trm9-deficient cells to mount a hypoxic response. We also demonstrate that the yeast cells were sensitive to the translational infidelity inducing hTRM9L expressing cells have a significant increase in mcm5U aminoglycoside antibiotic paromomycin (Kalhor & Clarke, and other tRNA modifications after paromomycin treatment, 2003). Cells deficient in Trm9 also display sensitivity to DNA relative to SW620-LacZ and that hTRM9L promotes global damaging agents (e.g. MMS and IR) and have a damage induced changes in tRNA modification. Finally, we show that loss of cell cycle progression defect (Begley et al, 2002, 2004, 2007; hTRM9L in certain tumours can be exploited as a potential Bennett et al, 2001; Chan et al, 2010). chemotherapeutic target since its absence renders tumour cells ALKBH8 is the most thoroughly characterized mammalian sensitive to aminoglycoside antibiotics, which induce mis- homolog of yeast Trm9 and ALKBH8 deficient cells are sensitive incorporation at specific codons leading to protein damage and to DNA damaging agents (Fu et al, 2010a). ALKBH8 makes selective tumour cell killing. the wobble uridine modifications mcm5U and mchm5U. The formation of mcm5U is required for the completion of the mcm5s2U, and mcm5Um modifications (Fu et al, 2010a,b; RESULTS Songe-Moller et al, 2010; van den Born et al, 2011). Mouse ALKBH8 has also been implicated in the recoding of stop Epigenetic silencing of hTRM9L in human primary cancers codons to promote the incorporation of selenocysteine into and cancer cell lines specific proteins (Songe-Moller et al, 2010). Compared to Published evidence and gene expression database mining yeast Trm9, ALKBH8 contains additional 2-oxoglutarate- and suggested that hTRM9L mRNA is down-regulated in human iron-dependent dioxygenase and RNA binding domains. The tumours due to epigenetic gene silencing (Flanagan et al, 2004; second yeast Trm9 homolog identified in mice and humans is Rhodes et al, 2004). To assess the extent of hTRM9L
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