A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters
Author
Kang, Hyun-JinCui, Yunxi
Yin, Holly
Scheid, Amy
Hendricks, William P. D.
Schmidt, Jessica
Sekulic, Aleksandar
Kong, Deming
Trent, Jeffrey M.
Gokhale, Vijay
Mao, Hanbin
Hurley, Laurence H.
Affiliation
Univ Arizona, Coll PharmUniv Arizona, Coll Sci,
Arizona Canc Ctr
Issue Date
2016-10-19
Metadata
Show full item recordPublisher
AMER CHEMICAL SOCCitation
A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters 2016, 138 (41):13673 Journal of the American Chemical SocietyRights
Copyright © 2016 American Chemical Society.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding-sites that drive hTERT expression, but this model cannot fully account for differences in wild-type (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here, we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing. We show that promoter mutations exert a detrimental effect on the folding of one of these G-quadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression produces cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and induction of senescence by decreasing telomerase activity and telomere length. We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress, hTERT.Note
Publication Date (Web): September 19, 2016. 12 month embargo.ISSN
0002-78631520-5126
Version
Final accepted manuscriptSponsors
National Science Foundation [CH-1609514, CHE-1415883]; National Institutes of Health [5R01CA153821, 1R01GM085585]; Stand Up To Cancer Melanoma Research Alliance/Melanoma Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0612]Additional Links
http://pubs.acs.org/doi/abs/10.1021/jacs.6b07598ae974a485f413a2113503eed53cd6c53
10.1021/jacs.6b07598