PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells

Abstract

Epithelial-mesenchymal transition (EMT) plays an essential role in organogenesis and contributes to a host of pathologies including carcinogenesis. Hypoxia 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 down-regulated SIRT1 expression primarily at the transcriptional level by reducing the occupancy of the transcriptional activator Sp1 on the proximal promoter of SIRT1 gene in a SUMOylation dependent manner. Further analysis revealed that the SUMO E3 ligase PIASy 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 specimen indicated that PIASy expression was positively, whereas SIRT1 expression was inversely, correlated with cancer aggressiveness. In summary, our work has identified a novel pathway that links SIRT1 down-regulation to hypoxia induced EMT in cancer cells and as such shed light in the development of novel anti-tumor therapeutics.