Profound functional switch of key regulatory factors may play a major role in homeostasis and disease. Dysregulation of circadian rhythm (CR) is strongly implicated in cancer with mechanisms poorly understood. We report here that the function of REV-ERBα, a major CR regulator of the orphan nuclear receptor subfamily, is dramatically altered in tumors in both its genome binding and functional mode. Loss of CR is linked to a functional inversion of REV-ERBα from a repressor in control of CR and metabolic gene programs in normal tissues to a strong activator in different cancers. Through changing its association from NCoR/HDAC3 corepressor complex to BRD4/p300 coactivators, REV-ERBα directly activates thousands of genes including tumorigenic programs such as MAPK and PI3K-Akt signaling. Functioning as a master transcriptional activator, REV-ERBα partners with pioneer factor FOXA1 and directly stimulates a large number of signaling genes, including multiple growth factors, receptor tyrosine kinases, RASs, AKTs, and MAPKs. Moreover, elevated REV-ERBα reprograms FOXA1 to bind new targets through a BRD4-mediated increase in local chromatin accessibility. Pharmacological targeting with SR8278 diminishes the function of both REV-ERBα and FOXA1 and synergizes with BRD4 inhibitor in effective suppression of tumorigenic programs and tumor growth. Thus, our study revealed a functional inversion by a CR regulator in driving gene reprogramming as an unexpected paradigm of tumorigenesis mechanism and demonstrated a high effectiveness of therapeutic targeting such switch.
Proceedings of the National Academy of Sciences of the United States of America. 2024 Oct 09 [Epub]
Yatian Yang, Xiong Zhang, Demin Cai, Xingling Zheng, Xuan Zhao, June X Zou, Jin Zhang, Alexander D Borowsky, Marc A Dall'Era, Eva Corey, Nicholas Mitsiades, Hsing-Jien Kung, Xinbin Chen, Jian Jian Li, Michael Downes, Ronald M Evans, Hong-Wu Chen
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817., Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037., Department of Surgical & Radiological Sciences, University of California-Davis, Davis, CA 95616., Department of Pathology and Laboratory Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817., Department of Urologic Surgery, School of Medicine, University of California Davis, Sacramento, CA 95817., Department of Urology, University of Washington, Seattle, WA 98195., Department of Internal Medicine, Division of Hematology and Oncology, School of Medicine, University of California Davis, Sacramento, CA 95817., Department of Radiation Oncology, School of Medicine, University of California Davis, Sacramento, CA 95817.