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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：
10006066
负责人：
Jennifer Marie Spangle
金额：
$ 24.9万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006066
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 Chromatin Remodeling Factor 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 Exposure to Foundations Future Gene Expression Genes Genetic Genetic Transcription Genomics Goals Growth Hematologic Neoplasms Histones Human In Vitro Infrastructure 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 Personnel Resources Science Signal Transduction Solid Solid Neoplasm Structure Testing Therapeutic Translations Treatment Efficacy Tumor Cell Line 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 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.

项目总结