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

项目摘要 缺氧诱导因子(HIF)是由α和β亚基组成的异源二聚体转录因子 调节对氧气供应减少的反应。已鉴定出三种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控因子，其蛋白 产品可促进癌症的生长、侵袭和转移。然而，HIF-1和HIF-2各自控制 调控癌症进展的不同方面的独特靶基因的转录。分子 HIF-1和HIF-2对反式激活的差异调控机制尚不清楚。 了解HIF-1和HIF-2介导的反式激活的调节机制将对 了解和治疗人类癌症。我的长期目标是阐明监管机制 潜在的HIF-1和HIF-2介导的人类癌症的反式激活，以确定治疗靶点，以 开发治疗人类癌症的有效药物。我鉴定了一种组蛋白去甲基酶，朱蒙吉 含有结构域的蛋白(JMJD)2C，它选择性地与缺氧诱导因子-1α结合并刺激缺氧诱导因子-1介导的 人乳腺癌细胞的反式激活。但JMJD2C不能与HIF-2α相互作用，也不能调节HIF-2 靶基因转录。我还发现JMJD2C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，我将检验一个假设，即JMJD2C促进人类 通过共激活HIF-1，乳腺癌的生长和转移，我将发现新的JMJD2C抑制剂，可能 对人类乳腺癌的治疗具有重要价值。在指导的K99阶段，我将研究分子机制 JMJD2C选择性共激活人乳腺癌细胞HIF-1并鉴定JMJD2C控制 HIF-1在全基因组范围内的靶向基因。在独立的R00阶段，我将通过以下方式定义机制 其中JMJD2C促进人乳腺癌的生长和转移，并寻找新的JMJD2C抑制剂。 该项目的成功完成将为分子机制提供创新的见解 乳腺癌中HIF-1和HIF-2介导的反式激活的潜在差异调控。它还将 确定新的治疗靶点，为乳腺癌的治疗提供潜在的工具。要实现 为了实现提出的目标，我组建了一个强大的指导团队，由格雷格·L·塞门扎博士(导师)、 国际公认的HIF-1和癌症生物学领域的领导者，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，国际公认的刘军博士(合作者) 是药物发现方面的专家。为了成功完成拟议的研究，我将接受鼠标方面的培训 人类癌症的原位和尾静脉模型，全基因组芯片序列和mRNA-序列分析，以及高密度脂蛋白 通过药物筛选，并将获得癌症生物学、生物信息学和药物方面的高级知识 在获奖期间，在负责任的研究行为方面进行发展以及全面培训。 总体而言，约翰霍普金斯大学医学院和 彭博公共卫生学院将推动成功完成拟议的研究，Soltify 并扩展我的专业知识，并向我保证成功地过渡到一名独立调查员。

Project Summary Hypoxia-inducible factors (HIFs), heterodimeric transcription factors consisting of α and β 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-1α and stimulates HIF-1-mediated transactivation in human breast cancer cells. But JMJD2C fails to interact with HIF-2α 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.