Molecular mechanisms of hypoxic transcriptional response
Hypoxic microenvironments are frequently found in solid tumors as a result of an imbalance between oxygen supply and consumption. Tumor hypoxia is a major therapeutic concern since it reduces the effectiveness of radiotherapy and some oxygen-dependent cytotoxic agents. Moreover, hypoxia is a driving force for malignant progression and tumor metastasis.
Evidence indicates that the effect of hypoxia on malignant progression and tumor metastasis is mainly controlled by hypoxia-mediated activation of angiogenesis, anaerobic metabolism, and other processes that enable tumor cells to survive or escape their oxygen-deficient environment. The overall goal of my laboratory is to define the molecular mechanisms of how hypoxia inducible genes are activated. Through these studies, we hope to generate therapeutic strategies to inhibit HIF target gene induction for solid tumor treatment.
The role of hypoxia inducible factors (HIFs), HIF-1 and HIF-2 in hypoxic transcriptional response is well established. However, we recently determined that HIF itself is not sufficient for hypoxic inducible gene activation and other transcription factors such as STAT3 and USF2 are also activated by hypoxia and required for HIF target gene activation. We also found that STAT3 and USF2 activate HIF target genes by recruiting histone acetylases CBP and p300 while HIF activates HIF target genes by recruiting SWI/SNF chromatin remodeling complex and JMJD6 histone demethylase. Furthermore, we found that STAT3 or USF2 are specifically required for HIF1 or HIF2 target gene activation, respectively. Additional data indicated that HIF1 or HIF2 specific partners STAT3 or USF2 are important for target gene specificity of HIF1 and HIF2 in hypoxia response. Thus, we solved the molecular mechanism of how the closely related HIF1 and HIF2 proteins activate distinct target genes, a long-lasting question in the hypoxia field.
Human genes contain introns that need to be removed during RNA splicing. However, RNA splicing is not an automatic process, but a regulated step for human gene expression. We found that normoxic cells often express HIF target genes as intron-containing, or exon-skipping mRNAs that made less functional or no proteins. Following HIF activation, HIF target gene transcription was increased. Importantly, the RNA splicing of HIF target genes was also increased by hypoxia. These data indicated that hypoxia not only enhances HIF target gene transcription, also increases RNA splicing of HIF regulated genes. We are determining the molecular mechanism concerning how hypoxia promotes RNA splicing of HIF target genes.
Johnny Sena, Molecular Biology
Aya Murakami, Molecular Biology
(Complete list of publications at https://profiles.ucdenver.edu/display/225660)
Befani C, Mylonis I, Gkotinakou IM, Georgoulias P, Hu CJ, Simos G, Liakos P. Cobalt stimulates HIF-1-dependent but inhibits HIF-2-dependent gene expression in liver cancer cells. Int J Biochem Cell Biol. 2013 Nov; 45(11):2359-68.
Sena JA, Wang L, Hu CJ. BRG1 and BRM chromatin-remodeling complexes regulate the hypoxia response by acting as a coactivator for a subset of HIF target genes. Mol Cell Biol. 2013 Oct; 33(19):3849-63.
Pawlus MR, Hu CJ. Enhanceosomes as integrators of hypoxia inducible factor (HIF) and other transcription factors in the hypoxic transcriptional response. Cell Signal. 2013 Sep; 25(9):1895-903.
You Q, Holt M, Yin H, Li G, Hu CJ, Ju C. Role of hepatic resident and infiltrating macrophages in liver repair after acute injury. Biochem Pharmacol. 2013 Sep 15;86(6):836-43.
Pawlus MR, Wang L, Murakami A, Dai G, Hu CJ. STAT3 or USF2 Contributes to HIF Target Gene Specificity. PLoS One. 2013 Aug 21; 8(8):e72358.
Pawlus MR, Wang L, Hu CJ. STAT3 and HIF1a cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells. Oncogene. 2013 Apr 22.
Pawlus MR, Wang L, Ware K, Hu CJ. Upstream stimulatory factor 2 and hypoxia-inducible factor 2a (HIF2a) cooperatively activate HIF2 target genes during hypoxia. Mol Cell Biol. 2012 Nov; 32(22):4595-610.
Hu CJ, Sataur A, Wang L, Chen H, Simon MC. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Mol Biol Cell. 2007 Nov; 18(11):4528-42.
Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity. Cancer Cell 2007 Apr; 11(4):335-347.
Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC. Acute postnatal ablation of HIF-2alpha results in anemia. Proc Natl Acad Sci USA 2007 Feb 13; 104(7):2301-2306.
Diez H, Fischer A, Winkler A, Hu CJ, Hatzopoulos A, Breier G, Gessler M. Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp Cell Res 2007 Jan 1; 313 (1):1-9
Hu CJ, Iyer S, Sataur A, Covello KL, Chodosh LA, Simon MC. Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1a) and HIF-2a in stem cells. Mol Cell Biol 2006 May; 26 (9):3514-3526.
Covello KL, Kehler J, Yu HW, Gordan JD, Arsham AM, HU CJ, Labosky PA, Simon MC, Keith B. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 2006 Mar 1; 20 (5):557-570.
Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 2003 Dec; 23 (24):9361-9374.