Functional inversion of circadian regulator REV-ERBα leads to tumorigenic gene reprogramming.

Autor:	Yang Y; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817., Zhang X; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817., Cai D; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817., Zheng X; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817., Zhao X; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037., Zou JX; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817., Zhang J; Department of Surgical & Radiological Sciences, University of California-Davis, Davis, CA 95616., Borowsky AD; Department of Pathology and Laboratory Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817., Dall'Era MA; Department of Urologic Surgery, School of Medicine, University of California Davis, Sacramento, CA 95817., Corey E; Department of Urology, University of Washington, Seattle, WA 98195., Mitsiades N; Department of Internal Medicine, Division of Hematology and Oncology, School of Medicine, University of California Davis, Sacramento, CA 95817.; Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817., Kung HJ; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817., Chen X; Department of Surgical & Radiological Sciences, University of California-Davis, Davis, CA 95616., Li JJ; Department of Radiation Oncology, School of Medicine, University of California Davis, Sacramento, CA 95817., Downes M; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037., Evans RM; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037., Chen HW; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817.; Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817.; Veterans Affairs Northern California Health Care System-Mather, Mather, CA 95655.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Oct 15; Vol. 121 (42), pp. e2411321121. Date of Electronic Publication: 2024 Oct 09.
DOI:	10.1073/pnas.2411321121
Abstrakt:	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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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