Hypoxia-inducible factors (HIFs), heterodimeric transcription factors consisting of ? and ? subunits, are master regulators of responses to reduced O2 availability. Three HIFs (HIF-1, HIF-2, and HIF-3) have been identified. HIF-1 and HIF-2 are two key regulators that activate transcription of over 1000 target genes, whose protein products promote cancer growth, invasion, and metastasis. However, HIF-1 and HIF-2 each controls transcription of unique target genes that regulate different aspects of cancer progression. The molecular mechanism for differential regulation of transactivation by HIF-1 vs HIF-2 is not well understood. Understanding regulatory mechanisms of HIF-1- and HIF-2-mediated transactivation will have implications for understanding and treating human cancer. My long-term goals are to elucidate regulatory mechanisms underlying HIF-1- and HIF-2-mediated transactivation in human cancers, to identify therapeutic targets, to develop effective drugs for treatment of human cancers. I have identified a histone demethylase, jumonji domain containing protein (JMJD) 2C, which selectively binds to HIF-1? and stimulates HIF-1-mediated transactivation in human breast cancer cells. But JMJD2C fails to interact with HIF-2? or to regulate HIF-2 target gene transcription. I also found that JMJD2C is highly amplified in human breast cancers and promotes breast cancer growth and metastasis. In this project, I will test a hypothesis that JMJD2C promotes human breast cancer growth and metastasis by coactivating HIF-1, and I will identify novel JMJD2C inhibitors that may be valuable for human breast cancer therapy. In the mentored K99 phase, I will study molecular mechanisms by which JMJD2C selectively coactivates HIF-1 in human breast cancer cells and identify JMJD2C-controlled HIF-1 target genes on a genome-wide scale. In the independent R00 phase, I will define the mechanisms by which JMJD2C promotes human breast cancer growth and metastasis and identify novel JMJD2C inhibitors. The successful completion of the project will provide innovative insights into the molecular mechanism underlying differential regulation of HIF-1- and HIF-2-mediated transactivation in breast cancer. It will also identify a novel therapeutic target and provide potential tools for breast cancer treatment. To achieve the proposed goals, I have assembled a strong mentoring team consisting of Dr. Gregg L. Semenza (Mentor), an internationally recognized leader in the field of HIF-1 and cancer biology, Dr. Saraswati Sukumar (Co-mentor), a nationally recognized expert in breast cancer, Dr. Shyam Biswal (Collaborator), a nationally recognized expert in genome-wide transcriptional analysis, and Dr. Jun Liu (Collaborator), an internationally recognized expert in drug discovery. To successfully accomplish the proposed research, I will obtain training in mouse orthotopic and tail vein models of human cancers, genome-wide ChIP-seq and mRNA-seq analyses, and high- throughput drug screening, and will acquire advanced knowledge in cancer biology, bioinformatics, and drug development as well as comprehensive training in responsible conduct of research during the award period. Overall, the excellent environment of research training at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health will facilitate the successful completion of the proposed research, solidify and expand my expertise, and assure me to make a successful transition to an independent investigator.
Breast cancer is the most frequent cancer in women. HIF-1 activation contributes to breast cancer progression and is highly associated with breast cancer patient mortality. This project aims to delineate molecular mechanisms by which a histone demethylase JMJD2C selectively coactivates HIF-1 and promotes breast cancer progression and to identify novel JMJD2C inhibitors, which may offer novel molecular targets and tools for breast cancer therapy. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.
|Luo, Weibo; Chen, Ivan; Chen, Yan et al. (2016) PRDX2 and PRDX4 are negative regulators of hypoxia-inducible factors under conditions of prolonged hypoxia. Oncotarget 7:6379-97|
|Xiang, Lisha; Gilkes, Daniele M; Hu, Hongxia et al. (2015) HIF-1Î± and TAZ serve as reciprocal co-activators in human breast cancer cells. Oncotarget 6:11768-78|
|Chapiro, Julius; Sur, Surojit; Savic, Lynn Jeanette et al. (2014) Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. Clin Cancer Res 20:6406-17|
|Takano, Naoharu; Peng, Ying-Jie; Kumar, Ganesh K et al. (2014) Hypoxia-inducible factors regulate human and rat cystathionine Î²-synthase gene expression. Biochem J 458:203-11|
|Luo, Weibo; Lin, Benjamin; Wang, Yingfei et al. (2014) PHD3-mediated prolyl hydroxylation of nonmuscle actin impairs polymerization and cell motility. Mol Biol Cell 25:2788-96|
|Hu, Hongxia; Takano, Naoharu; Xiang, Lisha et al. (2014) Hypoxia-inducible factors enhance glutamate signaling in cancer cells. Oncotarget 5:8853-68|
|Xiang, Lisha; Gilkes, Daniele M; Chaturvedi, Pallavi et al. (2014) Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer. J Mol Med (Berl) 92:151-64|
|Wang, Ting; Gilkes, Daniele M; Takano, Naoharu et al. (2014) Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci U S A 111:E3234-42|
|Xiang, Lisha; Gilkes, Daniele M; Hu, Hongxia et al. (2014) Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype. Oncotarget 5:12509-27|
|Cai, Zheqing; Luo, Weibo; Zhan, Huiwang et al. (2013) Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart. Proc Natl Acad Sci U S A 110:17462-7|