The PI3K/AKT Pathway Regulates Histone H3 Modification

PI3K/AKT 通路调节组蛋白 H3 修饰

基本信息

批准号：
9243133
负责人：
Jennifer Marie Spangle
金额：
$ 13.61万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243133
关键词：
Address Affect Affinity American Cancer Society Biology Breast Breast Cancer Model Breast Cancer cell line Cancer Biology Cancerous Cell Survival Cell physiology Chromatin Clinical Clinical Research Communities Competence DNA Sequence Alteration Data Development Disease Drug Combinations Drug resistance EGFR inhibition EZH2 gene Epigenetic Process Equilibrium Ethics Event Excision Foundations Future Gene Expression Genes Genetic Genetic Transcription Genomics Goals Growth Hematologic Neoplasms Histones Human In Vitro Journals Knowledge Lysine MLL gene Malignant Neoplasms Manuscripts Mediating Mentors Metabolism Methylation Methyltransferase Modification Molecular Mutate Mutation Nucleosomes Oncogenic Oncoproteins Output PI3K/AKT PIK3CA gene PTEN gene Pathway interactions Peer Review Pharmacologic Substance Phosphorylation Proto-Oncogene Proteins c-akt Publishing Regimen Regulation Reporting Research Research Infrastructure Research Personnel Resources Science Signal Transduction Solid Solid Neoplasm Testing Therapeutic Translations Treatment Efficacy Tumor Cell Line Tumorigenicity Viral Work Xenograft Model cancer therapy cancer type career cell growth clinical application histone demethylase histone modification in vivo in vivo Model inhibitor/antagonist insight malignant breast neoplasm medical schools novel novel therapeutics outcome forecast permissiveness pre-clinical promoter response targeted treatment tumor tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY PI3K/AKT pathway activation, most commonly occurring through PIK3CA mutation or PTEN inactivation, deregulates cell growth, metabolism, and cell survival and is a common and significant event in human cancer. Research now suggests that cancer is both a genetic and epigenetic disease, as changes to the chromatin landscape frequently occur. High levels of the H3K4me3 mark, indicative of transcriptional competence, is associated with a poor prognosis in some cancer types. The H3K4 histone demethylase KDM5A may mediate a drug resistant state in response to EGFR inhibition in PI3K-mutated cancers. Moreover, AKT previously was shown to decrease H3K27me3 through the phosphorylation of the H3K27 methyltransferase EZH2. I therefore investigated whether PI3K/AKT regulates transcriptional competence. My preliminary research and first, first- authored manuscript from my postdoctoral research demonstrate that AKT promotes cell growth by directly regulating KDM5A and increasing H3K4me3. These data provide the foundation for my future research goals described below. My immediate career goals are to ethically conduct high quality science and to publish my research in top tier, peer reviewed journals, such that I can become an independent investigator at the intersection of chromatin biology and oncogenic signaling. My immediate research-oriented goals are 100% embodied by the research plan I propose for the K99/R00. Within this proposal, I plan to first develop of a comprehensive understanding of how oncogenic PI3K/AKT promotes H3K4me3 (Aim 1). Because H3K4me3 has been reported as elevated in some solid cancers including breast cancer, I will generate and utilize preclinical xenograft models to define a strategy to reduce H3K4me3 in breast cancer (Aim 2). Finally, additional mechanisms by which oncogenic PI3K/AKT promotes transcriptional competence will be investigated, focusing on the functional consequence(s) of AKT-mediated H3T45 phosphorylation (Aim 3). Completion of these aims will provide additional understanding of the mechanistic underpinnings of PI3K/AKT signal transduction, and will inform future therapeutic regimens in PI3K-activated breast and other cancers. My doctoral research investigated the mechanisms by which a virally encoded oncoprotein activates AKT and mTORC1 to promote translation and oncogenic growth. Currently I am an American Cancer Society fellow in Dr. Tom Roberts' lab identifying mechanisms by which PI3K/AKT mediate transcriptional competence. These ongoing opportunities have extensively prepared me to address my overarching career goal to expose novel mechanisms by which PI3K deregulation drives cancer and exploit this understanding to develop durable and efficacious therapies for cancer. My mentor, the DFCI Cancer Biology department, and the larger DFCI and Harvard Medical School community are well-equipped and committed to providing me with the necessary resources and infrastructure to address the aims outlined in my research plan and work towards the accomplishment of my long-term career goals.

项目摘要 PI3K/AKT途径激活，最常见于PIK3CA突变或PTEN失活，消除细胞生长，代谢和细胞存活，是人类癌症中常见且重要的事件。现在的研究表明，随着染色质的变化，癌症既是遗传疾病又是表观遗传疾病景观经常发生。高水平的H3K4me3标记，指示转录能力，是与某些癌症类型的预后不良有关。 H3K4组蛋白脱甲基酶KDM5A可能介导 PI3K突变癌中EGFR抑制作用的抗药性状态。而且，以前是通过H3K27甲基转移酶EZH2的磷酸化可降低H3K27me3。我因此研究了PI3K/AKT是否调节转录能力。我的初步研究，首先我的博士后研究撰写的手稿表明，Akt直接促进细胞生长调节KDM5A并增加H3K4me3。这些数据为我未来的研究目标奠定了基础如下所述。我的直接职业目标是在道德上进行高质量的科学，并将我的研究发表在顶级，同行评审的期刊，使我可以成为染色质交集的独立研究者生物学和致癌信号传导。我的直接以研究为导向的目标是100％由研究所体现的我为K99/R00提出了计划。在此提案中，我计划首先开发全面的了解致癌PI3K/AKT如何促进H3K4ME3（AIM 1）。因为H3K4Me3一直据报道，包括乳腺癌在内的一些固体癌症中升高，我将产生并利用临床前异种移植模型定义了减少乳腺癌中H3K4ME3的策略（AIM 2）。最后，致癌PI3K/AKT促进转录能力的其他机制将是研究了，重点是Akt介导的H3T45磷酸化的功能后果（AIM 3）。这些目标的完成将提供对机械基础的更多理解 PI3K/AKT信号转导，并将为PI3K激活的乳房和其他其他治疗方案提供信息癌症。我的博士研究调查了病毒编码的癌蛋白激活AKT和 MTORC1促进翻译和致癌生长。目前，我是美国癌症协会的研究员汤姆·罗伯茨（Tom Roberts）博士的实验室识别PI3K/AKT介导转录能力的机制。这些持续的机会已经为我做好了解决我总体职业目标的准备，以揭露小说 PI3K放松管制会驱动癌症并利用这种理解以发展的机制癌症耐用且效率的疗法。我的导师，DFCI癌症生物学系和较大的DFCI和哈佛医学院社区设备齐全，并致力于为我提供必要的资源和基础设施，以解决我的研究计划中概述的目标，并致力于实现我的长期职业目标。