Stanniocalcin-2 is a HIF-1 target gene that promotes cell proliferation in hypoxia.
Stanniocalcin-2 (STC2), the paralog of STC1, has been suggested as a novel target of oxidative stress response to protect cells from apoptosis. The expression of STC2 has been reported to be highly correlated with human cancer development. In this study, we reported that STC2 is a HIF-1 target gene and is involved in the regulation of cell proliferation. STC2 was shown to be up-regulated in different breast and ovarian cancer cells, following exposure to hypoxia. Using ovarian cancer cells (SKOV3), the underlying mechanism of HIF-1 mediated STC2 gene transactivation was characterized. Hypoxia-induced STC2 expression was found to be HIF-1alpha dependent and required the recruitment of p300 and HDAC7. Using STC2 promoter deletion constructs and site-directed mutagenesis, two authentic consensus HIF-1 binding sites were identified. Under hypoxic condition, the silencing of STC2 reduced while the overexpression of STC2 increased the levels of phosphorylated retinoblastoma and cyclin D in both SKOV3 and MCF7 cells. The change in cell cycle proteins correlated with the data of the serial cell counts. The results indicated that cell proliferation was reduced in STC2-silenced cells but was increased in STC2-overexpressing hypoxic cells. Solid tumor progression is usually associated with hypoxia. The identification and functional analysis of STC2 up-regulation by hypoxia, a feature of the tumor microenvironment, sheds light on a possible role for STC2 in tumors.
Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Alice Y S
AY
Law
Chris K C
CK
Wong
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004220:Disulfides / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D026121:Indole Alkaloids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D020218:Response Elements / Q000235:genetics; D013997:Time Factors
D018797:Cell Cycle Proteins; D004220:Disulfides; D006023:Glycoproteins; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026121:Indole Alkaloids; D036341:Intercellular Signaling Peptides and Proteins; C114997:STC2 protein, human; C001598:chetomin; C012589:trichostatin A; D008156:Luciferases; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C543273:HDAC7 protein, human; D006655:Histone Deacetylases