Yinghui Li1, Qi-Ling Zhou1,6, Wenjie Sun2, Prashant Chandrasekharan3, Hui Shan Cheng1, Zhe Ying4,5, Manikandan Lakshmanan1, Anandhkumar Raju1, Daniel G. Tenen6,7, Shi-Yuan Cheng8, Kai-Hsiang Chuang3, Jun Li4,5, Shyam Prabhakar2, Mengfeng Li4,5, Vinay Tergaonkar1*
1 Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
2 Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore 138672, Singapore
3 Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Agency for Science, Technology and Research Singapore, 11 Biopolis Way, #02-02 Helios, Singapore 138667, Singapore
4 Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, China.
5 Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou, Guangdong, China.
6 Cancer Science Institute of Singapore, Singapore
7 Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts, USA
8 Department of Neurology, Northwestern Brain Tumor Institute, Center for Genetic Medicine & The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, USA
* Correspondence: Vinay Tergaonkar. email@example.com
Published online in Nature Cell Biology on 21 September 2015.
Transcriptional reactivation of TERT, the catalytic subunit of telomerase is necessary for cancer progression in about 90% of human cancers. The recent discovery of 2 prevalent somatic mutations - C250T and C228T in the TERT promoter in various cancers has provided insight into a plausible mechanism of TERT reactivation. Although the two hotspot mutations create a similar binding motif for E-twenty-six (ETS) transcription factors, we show that they are functionally distinct, in that the C250T unlike the C228T TERT promoter is driven by non-canonical NF-κB signalling. We demonstrate that binding of ETS to mutant TERT promoter is insufficient in driving its transcription but this process requires non-canonical NF-κB signalling for stimulus responsiveness, sustained telomerase activity and hence cancer progression. Our findings highlight a previously unrecognized role of non-canonical NF-κB signalling in tumorigenesis and elucidate a fundamental mechanism for TERT reactivation in cancers, which if targeted could have immense therapeutic implications.
Figure legend: Proposed model for telomerase reactivation in human cancers harboring C250T TERT promoter mutation.
The critical “T” residue for ETS1/2-p52 cooperative binding is indicated in blue dashed box. The mutational hot spots are in red. TERT expression is low when ETS1/2 alone is bound at the C250T promoter. Upon activation of non-canonical NF-κB signalling via exogenous ligands (e.g. TWEAK) or constitutive NIK expression, p52 is recruited to the C250T promoter and cooperates with ETS factors to drive efficient TERT transcription. Enhanced TERT expression promotes telomerase activity, necessary for cancer progression .
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