PIASy stimulates HIF1α SUMOylation and negatively regulates HIF1α activity in response to hypoxia

The Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, E-Institutes of Shanghai Municipal Education Commission, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oncogene (Impact Factor: 8.46). 10/2010; 29(41):5568-78. DOI: 10.1038/onc.2010.297
Source: PubMed


Hypoxia-inducible factor-1α (HIF1α) is a crucial regulator of the cellular response to hypoxia through its regulation of genes that control erythropoiesis, angiogenesis and anaerobic metabolism. We have previously shown that HIF1α stability is regulated by SUMOylation under the hypoxic condition. However, how HIF1α became SUMOylated during hypoxia is still unknown. In this study we identify PIASy as a specific E3 ligase for hypoxia-induced HIF1α SUMOylation. Hypoxia promotes translocation of HIF1α to the nucleus to facilitate its binding to PIASy, enabling the conjugation of HIF1α by SUMO1. We further show that PIASy negatively regulates hypoxia-induced HIF1α stability and transactivation. Knocking down PIASy increases the angiogenic activity of endothelial cells. Moreover, we show an inverse relationship between expression of PIASy and tumor angiogenesis in colon cancer. Thus, we define an important role of PIASy in hypoxia signaling through promoting HIF1α SUMOylation.

Download full-text


Available from: Edward T H Yeh, Sep 22, 2014
  • Source
    • "For an example, mutational loss of the von Hippel–Lindau protein's ability to bind HIF-1α as part of the ubiquitin ligase complex that marks HIF-1α for proteasomal degradation increases HIF-1α protein levels and promotes renal tumorigenesis 60,61. Another emerging mechanism is posttranslational modification of HIF-1α by small ubiquitin-related modifier (SUMO) under hypoxia to initiate ubiquitin-mediated proteasomal degradation of HIF-1α 62,63. SUMOylation is regulated by activating enzymes (E1), conjugating enzymes (E2), and ligating enzymes (E3 ligases) and reversed by SUMO-specific isopeptidases (sentrin/SUMO-specific proteases [SENPs]) 64. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The expression of 15-lipoxygenase-1 (15-LOX-1) is downregulated in colon cancer and other major cancers, and 15-LOX-1 reexpression in cancer cells suppresses colonic tumorigenesis. Various lines of evidence indicate that 15-LOX-1 expression suppresses premetastatic stages of colonic tumorigenesis; nevertheless, the role of 15-LOX-1 loss of expression in cancer epithelial cells in metastases continues to be debated. Hypoxia, a common feature of the cancer microenvironment, promotes prometastatic mechanisms such as the upregulation of hypoxia-inducible factor (HIF)-1α, a transcriptional master regulator that enhances cancer cell metastatic potential, angiogenesis, and tumor cell invasion and migration. We have, therefore, tested whether restoring 15-LOX-1 in colon cancer cells affects cancer cells' hypoxia response that promotes metastasis. We found that 15-LOX-1 reexpression in HCT116, HT29LMM, and LoVo colon cancer cells inhibited survival, vascular endothelial growth factor (VEGF) expression, angiogenesis, cancer cell migration and invasion, and HIF-1α protein expression and stability under hypoxia. These findings demonstrate that 15-LOX-1 expression loss in cancer cells promotes metastasis and that therapeutically targeting ubiquitous 15-LOX-1 loss in cancer cells has the potential to suppress metastasis.
    Cancer Medicine 06/2014; 3(3). DOI:10.1002/cam4.222 · 2.50 Impact Factor
  • Source
    • "An earlier study of colon cancer demonstrated high PIAS4 expression with little angiogensis in colon cancer tissue, which was associated with enhanced HIF1α sumoylation and deactivation of HIF1α activity (Kang et al, 2010). By contrast, our study showed that induction of PIAS4 is positively correlated with induction of HIF1α. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The PIAS4 protein belongs to the family of protein inhibitors of activated STAT, but has since been implicated in various biological activities including the post-translational modification known as sumoylation. In this study, we explored the roles of PIAS4 in pancreatic tumourigenesis. Methods: The expression levels of PIAS4 in pancreatic cancer cells were examined. Cell proliferation and invasion was studied after overexpression and gene silencing of PIAS4. The effect of PIAS4 on hypoxia signalling was investigated. Results: The protein was overexpressed in pancreatic cancer cells compared with the normal pancreas. Gene silencing by PIAS4 small interfering RNA (siRNA) suppressed pancreatic cancer cell growth and overexpression of PIAS4 induced expression of genes related to cell growth. The overexpression of PIAS4 is essential for the regulation of the hypoxia signalling pathway. PIAS4 interacts with the tumour suppressor von Hippel-Lindau (VHL) and leads to VHL sumoylation, oligomerization, and impaired function. Pancreatic cancer cells (Panc0327, MiaPaCa2) treated with PIAS4 siRNA suppressed expression of the hypoxia-inducible factor hypoxia-inducible factor 1 alpha and its target genes JMJD1A, VEGF, and STAT3. Conclusion: Our study elucidates the role of PIAS4 in the regulation of pancreatic cancer cell growth, where the suppression of its activity represents a novel therapeutic target for pancreatic cancers.
    British Journal of Cancer 09/2013; 109(7). DOI:10.1038/bjc.2013.531 · 4.84 Impact Factor
  • Source
    • "PIASy has been identified as the E3 ligase for hypoxia-induced HIF-1α SUMOylation. As a result, PIASy negatively regulates HIF-1α stability and activity [110]. However, different SUMOylation inducers may have distinct efficiencies, as HIF-1α has also been reported to be stabilized with increased SUMOylation by RSUME, an enhancer of SUMO conjugation, during hypoxia [111]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Heterodimeric transcription factor hypoxia inducible factor-1 (HIF-1) functions as a master regulator of oxygen homeostasis in almost all nucleated mammalian cells. The fundamental process adapted to cellular oxygen alteration largely depends on the refined regulation on its alpha subunit, HIF-1α. Recent studies have unraveled expanding and critical roles of HIF-1α, involving in a multitude of developmental, physiological, and pathophysiological processes. This review will focus on the current knowledge of HIF-1α-targeting genes and its interacting proteins, as well as the concomitant functional relationships between them.
    International Journal of Biochemistry and Molecular Biology 07/2012; 3(2):165-78.
Show more