TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer
Abstract
Telomerase reverse transcriptase (hTERT) is involved in immortalization and survival of cancer cells. Recurring mutations in its promoter often lead to its reexpression in cancer. Therapies targeting hTERT activity have been challenging to develop, and none are in routine use. Using targeted functional genomics knockout screening in a human bladder cancer model, we found that transcription factor TRIM28 activates hTERT expression preferentially from the mutant promoter allele. We also revealed a therapeutically targetable mechanism whereby mTORC1-mediated phosphorylation of TRIM28 is required to activate hTERT transcription. This study describes an approach to functional screening of endogenous promoters and insights into TERT regulation, and it may aid clinicians in making informed decisions for precision therapy of cancer patients harboring hTERT promoter mutations.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 13, 2021
- Source ID
- 10.1073/pnas.2102423118
Entities
People
- Bassem B. Cheikh
- Dan Theodorescu
- Daniel V LaBarbera
- Evan P. Hass
- Molishree Joshi
- Neeraj Agarwal
- Qiong Zhou
- Robert T. Jones
- Sebastien Rinaldetti
- Simon R. V. Knott
- Thomas Cech
Organizations
- Anschutz Medical Campus
- Cedars-Sinai Medical Center
- Congressionally Directed Medical Research Programs
- University of Colorado