The role of JMJD2C in HIF-1 activation and breast cancer progression

描述（由申请人提供）：缺氧诱导因子（HIF），异二聚体转录因子，由？然后呢？亚基是对减少的O2可用性的反应的主调节器。已经鉴定了三种HIF（HIF-1、HIF-2和HIF-3）。HIF-1和HIF-2是激活1000多个靶基因转录的两个关键调节因子，其蛋白产物促进癌症生长、侵袭和转移。然而，HIF-1和HIF-2各自控制调节癌症进展不同方面的独特靶基因的转录。HIF-1与HIF-2对转录激活的差异调节的分子机制还不清楚。理解HIF-1和HIF-2介导的转录激活的调节机制将对理解和治疗人类癌症具有重要意义。我的长期目标是阐明HIF-1和HIF-2介导的人类癌症反式激活的调控机制，以确定治疗靶点，开发有效的药物治疗人类癌症。我已经确定了一个组蛋白去甲基化酶，jumonji域含有蛋白质（JM JD）2C，选择性地结合到HIF-1？并刺激人乳腺癌细胞中HIF-1介导的反式激活。但JMJD 2C不能与HIF-2相互作用？或调节HIF-2靶基因转录。我还发现JMJD 2C在人类乳腺癌中高度扩增，并促进乳腺癌的生长和转移。在这个项目中，我将测试一个假设，即JMJD 2C通过共激活HIF-1促进人类乳腺癌的生长和转移，我将确定新的JMJD 2C抑制剂，可能对人类乳腺癌治疗有价值。在指导K99阶段，我将研究JMJD 2C选择性共激活人类乳腺癌细胞中HIF-1的分子机制，并在全基因组范围内识别JMJD 2C控制的HIF-1靶基因。在独立的R 00阶段，我将定义JMJD 2C促进人类乳腺癌生长和转移的机制，并确定新的JMJD 2C抑制剂。该项目的成功完成将为乳腺癌中HIF-1和HIF-2介导的反式激活的差异调节的分子机制提供创新的见解。它还将确定一个新的治疗靶点，并为乳腺癌治疗提供潜在的工具。为了实现所提出的目标，我组建了一个强大的指导团队，由Gregg L。Semenza（导师），HIF-1和癌症生物学领域国际公认的领导者，Saraswati Sukumar博士（共同导师），全国公认的乳腺癌专家，Shyam Biswal博士（合作者），全国公认的全基因组转录分析专家，以及Jun Liu博士（合作者），国际公认的药物发现专家。为了成功完成拟议的研究，我将获得人类癌症的小鼠原位和尾静脉模型，全基因组ChIP-seq和mRNA-seq分析和高通量药物筛选方面的培训，并将获得癌症生物学，生物信息学和药物开发方面的先进知识，以及在奖励期间负责开展研究的全面培训。总的来说，约翰霍普金斯大学医学院和彭博公共卫生学院良好的研究培训环境将有助于成功完成拟议的研究，巩固和扩展我的专业知识，并确保我成功过渡到独立调查员。

DESCRIPTION (provided by applicant): 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.