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

Yinghui Li, Qi Ling Zhou, Wenjie Sun, Prashant Chandrasekharan, Hui Shan Cheng, Zhe Ying, Manikandan Lakshmanan, Anandhkumar Raju, Daniel G. Tenen, Shi Yuan Cheng, Kai Hsiang Chuang, Jun Li, Shyam Prabhakar, Mengfeng Li, Vinay Tergaonkar*

*Corresponding author for this work

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1327-1338
Number of pages12
JournalNature Cell Biology
Volume17
Issue number10
DOIs
StatePublished - Oct 3 2015

ASJC Scopus subject areas

  • Cell Biology

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    Li, Y., Zhou, Q. L., Sun, W., Chandrasekharan, P., Cheng, H. S., Ying, Z., Lakshmanan, M., Raju, A., Tenen, D. G., Cheng, S. Y., Chuang, K. H., Li, J., Prabhakar, S., Li, M., & Tergaonkar, V. (2015). Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. Nature Cell Biology, 17(10), 1327-1338. https://doi.org/10.1038/ncb3240