Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation.
Nat Cell Biol
; 17(10): 1327-38, 2015 Oct.
Article
em En
| MEDLINE
| ID: mdl-26389665
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.
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Base de dados:
MEDLINE
Assunto principal:
NF-kappa B
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Regiões Promotoras Genéticas
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Telomerase
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Mutação de Sentido Incorreto
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Proteína Proto-Oncogênica c-ets-1
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Proteína Proto-Oncogênica c-ets-2
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article