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Nat Cell Biol. 2015 Oct;17(10):1327-38. doi: 10.1038/ncb3240. Epub 2015 Sep 21.

Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation.

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Institute of Molecular and Cell Biology (IMCB), A∗STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
Cancer Science Institute of Singapore, 14 Medical Dr #12-01, Singapore 117599, Singapore.
Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore 138672, Singapore.
Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Agency for Science, Technology and Research Singapore, 11 Biopolis Way, #02-02 Helios, Singapore 138667, Singapore.
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou, Guangdong 510080, China.
Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
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, Illinois 60611, USA.


Transcriptional reactivation of TERT, the catalytic subunit of telomerase, is necessary for cancer progression in about 90% of human cancers. The recent discovery of two 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 the 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.

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