TY - JOUR
T1 - A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α
AU - Begley, Ulrike
AU - Sosa, Maria Soledad
AU - Avivar-Valderas, Alvaro
AU - Patil, Ashish
AU - Endres, Lauren
AU - Estrada, Yeriel
AU - Chan, Clement T.Y.
AU - Su, Dan
AU - Dedon, Peter C.
AU - Aguirre-Ghiso, Julio A.
AU - Begley, Thomas
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - Cancer
KW - HTRM9L
KW - Hypoxia
KW - TRNA modification
KW - Translation
UR - http://www.scopus.com/inward/record.url?scp=84874750617&partnerID=8YFLogxK
U2 - 10.1002/emmm.201201161
DO - 10.1002/emmm.201201161
M3 - Article
C2 - 23381944
AN - SCOPUS:84874750617
SN - 1757-4676
VL - 5
SP - 366
EP - 383
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 3
ER -