Hypoxia-inducible factor 3 is an oxygen-dependent transcription activator and regulates a distinct transcriptional response to hypoxia
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE54318 | GEO | 2017/01/13
SECONDARY ACCESSION(S): PRJNA236310
REPOSITORIES: GEO
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Project description:Hypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis. HIF induces the expression of several hundred genes under hypoxic conditions. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered as a negative regulator of the hypoxia response pathway by formation of inactive dimers between the HIF-3α and HIF-1α or HIF-2α subunit. However, the human HIF3A mRNA is subject to complex alternative splicing, which leads to production of both long and short HIF-3α variants. It has been shown recently that the long HIF-3α variants can form αβ dimers that possess transcriptional activation capacity, while the short splice variant inhibits hypoxia-inducible gene expression. Chromatin immunoprecipitation analyses of HIF-3α2 overexpression in Hep3B cells show that HIF-3α2 binding associates with canonical hypoxia response elements (5'-RCGTG-3') in the promoter regions of the erythropoietin (EPO) gene among others. Luciferase reporter assays show that the identified HIF-3α2 chromatin-binding regions are sufficient to promote transcription by HIF-3α2 and HIF-1. Furthermore, HIF-3α2 overexpression and knock-down studies by siRNA targeting the HIF3A gene show that EPO mRNA and protein levels are upregulated and downregulated, respectively. Taken together, the results show that HIF-3α2 is a transcription activator that is directly involved in erythropoietin signaling.
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Project description:Hypoxia has crucial functions in cervical cancer development and metastasis by inducing the level of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells. Here, we show that hypoxia-induced overexpression HIF-3α increased the expression of dozens of miRNAs, including miR-630. Stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Stable inhibition of miR-630 showed opposite features. Further experiment showed the activation of miR-630 was induced by hypoxia treatment. For the molecular mechanism, we used RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing experiments (ChIP-seq) to investigate the targets of HIF-3α. We showed that hypoxia induces expression of HIF-3α to activate miR-630 expression by directly binding to its promoter. Meanwhile, miR-630 positively regulates HIF-1α expression, but represses HIF-1α. Taken together, our findings implicate a novel hypoxia-induced HIF3a-miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells, and suggest HIF3a and miR630 might be applied as a potential biomarker and therapeutic target for cervical cancer.
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Project description:Hypoxia has crucial functions in cervical cancer development and metastasis by inducing the level of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells. Here, we show that hypoxia-induced overexpression HIF-3α increased the expression of dozens of miRNAs, including miR-630. Stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Stable inhibition of miR-630 showed opposite features. Further experiment showed the activation of miR-630 was induced by hypoxia treatment. For the molecular mechanism, we used RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing experiments (ChIP-seq) to investigate the targets of HIF-3α. We showed that hypoxia induces expression of HIF-3α to activate miR-630 expression by directly binding to its promoter. Meanwhile, miR-630 positively regulates HIF-1α expression, but represses HIF-1α. Taken together, our findings implicate a novel hypoxia-induced HIF3a-miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells, and suggest HIF3a and miR630 might be applied as a potential biomarker and therapeutic target for cervical cancer.
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