The PI3K/AKT Pathway Regulates Histone H3 Modification

项目总结

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.