title: Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy.
abstract: The 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 epithelial-mesenchymal 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.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Hwang-Verslues
authors.forename: Po-Hao
authors.initials: PH
authors.lastname: Chang
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Kuo
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Chiang
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chang
authors.forename: Tsung-Han
authors.initials: TH
authors.lastname: Hsieh
authors.forename: Fang-Yi
authors.initials: FY
authors.lastname: Su
authors.forename: Liu-Chen
authors.initials: LC
authors.lastname: Lin
authors.forename: Serena
authors.initials: S
authors.lastname: Abbondante
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Yang
authors.forename: Huan-Ming
authors.initials: HM
authors.lastname: Hsu
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.forename: King-Jen
authors.initials: KJ
authors.lastname: Chang
authors.forename: Jin-Yuh
authors.initials: JY
authors.lastname: Shew
authors.forename: Eva Y-H P
authors.initials: EY
authors.lastname: Lee
authors.forename: Wen-Hwa
authors.initials: WH
authors.lastname: Lee
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D027702:Organic Cation Transporter 1 / Q000502:physiology*; D056950:Period Circadian Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D015854:Up-Regulation / Q000235:genetics
chemical_list: D027702:Organic Cation Transporter 1; C421902:PER2 protein, human; D056950:Period Circadian Proteins
keywords: HIF1alpha; breast cancer stem cell