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

• Main Authors: Akıncılar, Semih Can, Chua, Joelle Yi Heng, Ng, Qin Feng, Chan, Claire Hian Tzer, Eslami-S, Zahra, Chen, Kaijing, Low, Joo-Leng, Arumugam, Surendar, Aswad, Luay, Chua, Clarinda, Tan, Iain Beehuat, DasGupta, Ramanuj, Fullwood, Melissa Jane, Tergaonkar, Vinay
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Medicine; Chromatin; Colorectal Neoplasms
• Online Access: https://hdl.handle.net/10356/169656
• Institution: Nanyang Technological University

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.