News archives


OCTOBER - DECEMBER 17

JULY - SEPTEMBER 17

APRIL - JUNE 17

JANUARY - MARCH 17

OCTOBER - DECEMBER 16

JULY - SEPTEMBER 16

APRIL - JUNE 16

JANUARY - MARCH 16

OCTOBER - DECEMBER 15

JULY - SEPTEMBER 15

APRIL - JUNE 15

JANUARY - MARCH 15

OCTOBER - DECEMBER 14

JULY - SEPTEMBER 14

APRIL - JUNE 14

JANUARY - MARCH 14

OCTOBER - DECEMBER 13

JULY - SEPTEMBER 13

APRIL - JUNE 13

JANUARY - MARCH 13

OCTOBER - DECEMBER 12

JULY - SEPTEMBER 12

APRIL - JUNE 12

JANUARY - MARCH 12

OCTOBER - DECEMBER 11

JULY - SEPTEMBER 11

APRIL - JUNE 11

JANUARY - MARCH 11

OCTOBER - DECEMBER 10

JULY - SEPTEMBER 10

APRIL - JUNE 10

JANUARY - MARCH 10

OCTOBER - DECEMBER 09

JULY - SEPTEMBER 09

APRIL - JUNE 09

JANUARY - MARCH 09

OCTOBER - DECEMBER 08

JULY - SEPTEMBER 08

APRIL - JUNE 08

JANUARY - MARCH 08

OCTOBER - DECEMBER 07

JULY - SEPTEMBER 07

APRIL - JUNE 07

JANUARY - MARCH 07

 
  current news   Press   selected story    
     
  20 September 2016  
 
Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression
 
 




Authors
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
*  Correspondence:
Vinay Tergaonkar, vinayt@imcb.a-star.edu.sg, 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.

Abstract
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.

For more information on Vinay TERGAONKAR's lab, please click here.