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

• 成果类型: Article
• 署名作者: Yang, Yatian; Zhang, Xiong; Cai, Demin; Zheng, Xingling; Zhao, Xuan; Zou, June X.; Zhang, Jin; Borowsky, Alexander D.; Dall'Era, Marc A.; Corey, Eva; Mitsiades, Nicholas; Kung, Hsing-Jien; Chen, Xinbin; Li, Jian Jian; Downes, Michael; Evans, Ronald M.; Chen, Hong-Wu
• 署名单位: University of California System; University of California Davis; Salk Institute; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; University of Washington; University of Washington Seattle; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8816
• DOI: 10.1073/pnas.2411321121
• 发表日期: 2024-10-15
• 关键词: nuclear receptors; cancer; transcription; corepressor; expression; clock; metabolism; repression; recruits; lethal

摘要

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-ERB alpha, 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-ERB alpha 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-ERB alpha directly activates thousands of genes including tumorigenic programs such as MAPK and PI3K-Akt signaling. Functioning as a master transcriptional activator, REV-ERB alpha 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-ERB alpha 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-ERB alpha 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.