title: Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation.
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.
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A∗STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Qi-Ling
authors.initials: QL
authors.lastname: Zhou
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore 138672, Singapore.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Sun
authors.affiliation: Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Agency for Science, Technology and Research Singapore, 11 Biopolis Way, #02-02 Helios, Singapore 138667, Singapore.
authors.forename: Prashant
authors.initials: P
authors.lastname: Chandrasekharan
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A∗STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Hui Shan
authors.initials: HS
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ying
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A∗STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Lakshmanan
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A∗STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Anandhkumar
authors.initials: A
authors.lastname: Raju
authors.affiliation: Cancer Science Institute of Singapore, 14 Medical Dr #12-01, Singapore 117599, Singapore.|Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.affiliation: 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.
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Agency for Science, Technology and Research Singapore, 11 Biopolis Way, #02-02 Helios, Singapore 138667, Singapore.
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Chuang
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore 138672, Singapore.
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: 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.
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A∗STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000074049:Cytokine TWEAK; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D014183:Transplantation, Heterologous; D048069:Tumor Necrosis Factors / Q000494:pharmacology
chemical_list: D000074049:Cytokine TWEAK; C494041:ETS1 protein, human; C494069:ETS2 protein, human; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D050784:Proto-Oncogene Protein c-ets-1; D050787:Proto-Oncogene Protein c-ets-2; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors; C509186:TERT protein, human; D019098:Telomerase