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Cancer Discov. 2016 Nov;6(11):1276-1291. Epub 2016 Sep 20.

Long-Range Chromatin Interactions Drive Mutant TERT Promoter Activation.

Author information

1
Division of Cancer Genetics and Therapeutics, Laboratory of NFκB Signaling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore.
2
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.
3
Cancer Science Institute, National University of Singapore, Singapore.
4
Division of Cancer Genetics and Therapeutics, Laboratory of NFκB Signaling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore. vinayt@imcb.a-star.edu.sg.
5
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.

Abstract

Cancer-specific TERT promoter mutations (-146C>T and -124C>T) have been linked to reactivation of the epigenetically silenced telomerase reverse transcriptase gene (TERT). Understanding how these single-nucleotide alterations drive TERT reactivation is a fundamental unanswered question and is key for making successful therapeutics. We show that unlike wild-type promoters, recruitment of the transcription factor GABPA specifically to mutant TERT promoters mediates long-range chromatin interaction and enrichment of active histone marks, and hence drives TERT transcription. CRISPR-mediated reversal of mutant TERT promoters, or deletion of its long-range interacting chromatin, abrogates GABPA binding and long-range interactions, leading to depletion of active histone marks, loss of POL2 recruitment, and suppression of TERT transcription. In contrast, de novo introduction of a TERT promoter mutation enables GABPA binding and upregulation of TERT via long-range interactions, acquisition of active histone marks, and subsequent POL2 recruitment. This study provides a unifying mechanistic insight into activation of mutant TERT promoters across various human cancers.

SIGNIFICANCE:

This study identifies a key mechanism by which cancer-specific mutant TERT promoters cause reactivation of TERT Because the mechanism uncovered here is not utilized by promoters that drive TERT in normal cells, this mechanism could be exploited to make inhibitors which have the potential to block telomerase function and hence the progression of up to 90% of human cancers. Cancer Discov; 6(11); 1276-91. ©2016 AACR.See related commentary by Min and Shay, p. 1212This article is highlighted in the In This Issue feature, p. 1197.

PMID:
27650951
DOI:
10.1158/2159-8290.CD-16-0177
[Indexed for MEDLINE]
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