Hwang-Verslues W.W.Chang P.-H.YUNG-MING JENGWEN-HUNG KUOChiang P.-H.YI-CHENG CHANGHsieh T.-H.Su F.-Y.Lin L.-C.Abbondante S.Yang C.-Y.Hsue H.-M.Yu J.-C.KING-JEN CHANGShewa J.-Y.Lee E.Y.-H.P.Lee W.-H.2020-03-062020-03-0620130027-8424https://www.scopus.com/inward/record.uri?eid=2-s2.0-84880667008&doi=10.1073%2fpnas.1222684110&partnerID=40&md5=00179e0ea7f5da76bd848a180b753b10https://scholars.lib.ntu.edu.tw/handle/123456789/473355The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of PER2 enhanced invasion and activated expression of epithelialmesenchymal transition (EMT) genes including TWIST1, SLUG, and SNAIL. This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. Hypoxia, a condition commonly observed in tumors, caused PER2 degradation and disrupted the PER2 repressor complex, leading to activation of EMT gene expression. This result was further supported by clinical data showing a significant negative correlation between hypoxia and PER2. Thus, our findings clearly demonstrate the tumor suppression function of PER2 and elucidate a pathway by which hypoxia promotes EMT via degradation of PER2.[SDGs]SDG3corepressor protein; histone deacetylase 2; octamer transcription factor 1; PER2 protein; transcription factor EZH2; transcription factor Slug; transcription factor Twist; article; breast carcinogenesis; cancer prognosis; controlled study; epithelial mesenchymal transition; gene control; gene expression; gene loss; genetic association; human; human cell; human tissue; hypoxia; priority journal; protein degradation; receptor down regulation; breast cancer stem cell; HIF1alpha; Anoxia; Breast Neoplasms; Cell Line, Tumor; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation; Humans; Organic Cation Transporter 1; Period Circadian Proteins; Promoter Regions, Genetic; Protein Processing, Post-Translational; Up-Regulationjournal article10.1073/pnas.1222684110238366622-s2.0-84880667008