Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer

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Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer
Title:
Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer
Other Titles:
Nucleic Acids Research
Keywords:
Publication Date:
14 June 2022
Citation:
Akıncılar, S. C., Chua, J. Y. H., Ng, Q. F., Chan, C. H. T., Eslami-S, Z., Chen, K., Low, J.-L., Arumugam, S., Aswad, L., Chua, C., Tan, I. B., DasGupta, R., Fullwood, M. J., & Tergaonkar, V. (2022). Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer. Nucleic Acids Research. https://doi.org/10.1093/nar/gkac479
Abstract:
Abstract Transcriptional reactivation of hTERT is the limiting step in tumorigenesis. While mutations in hTERT promoter present in 19% of cancers are recognized as key drivers of hTERT reactivation, mechanisms by which wildtype hTERT (WT-hTERT) promoter is reactivated, in majority of human cancers, remain unknown. Using primary colorectal cancers (CRC) we identified Tert INTeracting region 2 (T-INT2), the critical chromatin region essential for reactivating WT-hTERT promoter in CRCs. Elevated β-catenin and JunD level in CRC facilitates chromatin interaction between hTERT promoter and T-INT2 that is necessary to turn on hTERTexpression. Pharmacological screens uncovered salinomycin, which inhibits JunD mediated hTERT-T-INT2 interaction that is required for the formation of a stable transcription complex on the hTERT promoter. Our results showed for the first time how known CRC alterations, such as APC, lead to WT-hTERT promoter reactivation during stepwise-tumorigenesis and provide a new perspective for developing cancer-specific drugs.
License type:
Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
Funding Info:
This research / project is supported by the National Research Foundation - Competitive Research Program
Grant Reference no. : NRF-CRP17-2017-02

This research / project is supported by the Singapore Ministry of Education - Academic Research Fund Tier 2 grant
Grant Reference no. : MOET2EP30120-0009
Description:
This is the version of record an article accepted for publication in [Nucleic Acids Research] following peer review. The version of record Akıncılar, S. C., Chua, J. Y. H., Ng, Q. F., Chan, C. H. T., Eslami-S, Z., Chen, K., Low, J.-L., Arumugam, S., Aswad, L., Chua, C., Tan, I. B., DasGupta, R., Fullwood, M. J., & Tergaonkar, V. (2022). Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer. Nucleic Acids Research. https://doi.org/10.1093/nar/gkac479 is available online at: https://doi.org/10.1093/nar/gkac479
ISSN:
1362-4962
0305-1048
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