title: PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells.
abstract: Epithelial-mesenchymal transition (EMT) has an essential role in organogenesis and contributes to a host of pathologies, including carcinogenesis. Hypoxia (low oxygen supply) aids tumor metastasis in part by promoting EMT in cancer cells. The underlying mechanism whereby hypoxia orchestrates EMT remains poorly defined. Here we report that SIRT1, a multifaceted player in tumorigenesis, opposed ovarian cancer metastasis in vitro and in vivo by impeding EMT. Hypoxic stress downregulated the expression of SIRT1, primarily at the transcriptional level, by reducing the occupancy of the transcriptional activator Sp1 on the proximal promoter of the SIRT1 gene in a SUMOylation-dependent manner. Further analysis revealed that the SUMO E3 ligase PIASy (also known as PIAS4) was induced by hypoxia and prevented Sp1 from binding to the SIRT1 promoter. Conversely, knockdown of PIASy by small interfering RNA (siRNA) restored Sp1 binding and SIRT1 expression in cancer cells challenged with hypobaric hypoxia, reversed cancer cell EMT, and attenuated metastasis in vivo in nude mice. Importantly, analysis of human ovarian tumor specimens indicated that PIASy expression was positively, whereas SIRT1 expression was inversely, correlated with cancer aggressiveness. In summary, our work has identified a new pathway that links downregulation of SIRT1 to hypoxia-induced EMT in ovarian cancer cells and, as such, sheds light on the development of novel anti-tumor therapeutics.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing 210029, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Sun
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.forename: Junliang
authors.initials: J
authors.lastname: Chen
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.forename: Mayumi
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D058207:Sumoylation / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: EMT; Ovarian cancer; PIAS4; PIASy; SIRT1 transcription; SUMOylation