Ekta Khattar1, Pavanish Kumar2#, Chia Yi Liu1#, Semih Can Akıncılar1, Anandhkumar Raju1, Manikandan Lakshmanan1, Julien Jean Pierre Maury3, Yu Qiang4, Shang Li5, Ern Yu Tan6, Kam M. Hui5,7,8,9,10, Ming Shi11, Yuin Han Loh3, Vinay Tergaonkar1,9*.
1 Division of Cancer Genetics and Therapeutics, Laboratory of NFκB Signaling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673.
2 Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
3 Epigenetics and Cell Fates Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
4 Genome Institute of Singapore, A*STAR, Singapore.
5 Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore.
6 Department of General Surgery, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, 308433 Singapore.
7 National Cancer Centre, Singapore, Singapore.
8 Institute of Molecular and Cell Biology, A*STAR, Singapore.
9 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore.
10 Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore.
11 Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
# Equal Contribution
Vinay Tergaonkar, firstname.lastname@example.org, Institute of Molecular and Cell Biology (A*STAR), Proteos, 61, Biopolis Drive, 138673, Singapore. Ph +65-65869836; Fax +65-67791117.
The authors declare that no conflict of interest exists.
Published online in Journal of Clinical Investigation on 19 September 2016.
Transcriptional reactivation of telomerase reverse transcriptase (TERT) reconstitutes telomerase activity in majority of human cancers. Here we found that ectopic TERT expression increases cell proliferation, while acute reduction in TERT levels leads to dramatic loss of proliferation without any change in telomere length, suggesting that its effects could be telomere-independent. We observed that TERT determines the growth rate of cancer cells by directly regulating global protein synthesis independently of its catalytic activity. Genome-wide TERT binding across 5 cancer cell lines and 2 embryonic stem cell lines revealed that endogenous TERT, driven by mutant promoters or oncogenes, directly associates with the RNA polymerase III subunit RPC32 and enhances its recruitment to chromatin, resulting in increased RNA polymerase III occupancy and tRNA expression in cancers. TERT-deficient mice displayed marked delays in PyMT-induced mammary tumorigenesis, increased survival, and reductions in tRNA levels. Ectopic expression of either RPC32 or TERT restored tRNA levels and proliferation defects in TERT-depleted cells. Finally, we determined that levels of TERT and tRNA correlated in breast and liver cancer samples. Together, these data suggest a unifying mechanism by which TERT enhances translation in cells to regulate cancer cell proliferation.
Figure Legend: Homozygous deletion of Tert delays PyMT-driven breast cancer in vivo and leads to reduced tRNA expression. (A) Kaplan-Meier curves showing the tumor-free survival of PyMT Tert WT (n=21) and PyMT Tert KO (n=16) mice. Statistical analysis was done using two tailed student’s t test. P value is indicated in the graph and it was significant. (B) qPCR analysis showing levels of Pre-tRNA Tyr, Tert and Terc relative to Actin in PyMT Tert WT and PyMT Tert KO tumors. n≥3. Statistical analysis was done using two tailed student’s t test. * indicates p value <0.05 and significant, # indicates p value >0.05, non-significant.
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