Cheryl M Koh1#, Ekta Khattar2#, Shi Chi Leow2, Chia Yi Liu2, Julius Muller1, Wei Xia Ang1, Yinghui Li2, Guido Franzoso3, Shang Li4,5, Ernesto Guccione1,6* and Vinay Tergaonkar2,6*
1 Division of Cancer Genetics and Therapeutics, Laboratory of Methyltransferases in Development and Disease, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673.
2 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.
3 Department of Medicine, Imperial College London, London.
4 Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
5 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
6 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
# Equal Contribution.
*Correspondence: Ernesto Guccione, firstname.lastname@example.org; Ph +65-65869844,
OR Vinay Tergaonkar. email@example.com, Institute of Molecular and Cell Biology (A*STAR), Proteos, 61, Biopolis Drive, 138673, Singapore. Ph +65-65869836; Fax +65-67791117.
Published online in The Journal of Clinical Investigation on 20 April 2015.
Constitutively active MYC and reactivated telomerase often co-exist in cancers. While reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with co-factors, confers several growth advantages to cancer cells. It is known that the reactivation of TERT, the catalytic subunit of telomerase, is limiting for reconstituting telomerase activity in tumors. However, while reactivation of TERT has been functionally linked to the acquisition of several “hallmarks of cancers” in tumors, the molecular mechanisms by which this occurs, and if these mechanisms are distinct from the role of telomerase on telomeres is not clear. Here, we show that first generation TERT-null mice, unlike Terc-null mice, show delayed onset of MYC induced lymphomagenesis. We further show that TERT is a novel regulator of MYC stability in cancer. TERT stabilizes MYC levels on chromatin, contributing to either activation or repression of its target genes. Mechanistically, TERT regulates MYC ubiquitination and proteasomal degradation, and this effect of TERT is independent of its reverse transcriptase activity and role on telomeres. Based on these data, we conclude that reactivation of TERT, a direct transcriptional MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis.
Figure legend: Graphical model. TERT levels (which are limiting in reconstituting telomerase activity in normal cells) are upregulated by increased MYC in cancer cells. TERT, in turn, enhances MYC stability and function, thereby regulating its own levels and telomerase activity. This function of TERT does not require Terc, and is independent of its telomere function. Enhanced MYC stability and function in high TERT and high MYC cells (due to this feed forward mechanism) leads to enhanced oncogenesis due to downstream targets of MYC, which are known to regulate aspects of cell cycle, proliferation and metabolism.
For more information on Ernesto GUCCIONE's laboratory, please click here.
For more information on Vinay TERGAONKAR's laboratory, please click here.