# The PI3K/AKT Pathway Regulates Histone H3 Modification

> **NIH NIH R00** · EMORY UNIVERSITY · 2020 · $248,989

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10006066
- **Project number:** 5R00CA204601-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Jennifer Marie Spangle
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,989
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006066

## Citation

> US National Institutes of Health, RePORTER application 10006066, The PI3K/AKT Pathway Regulates Histone H3 Modification (5R00CA204601-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10006066. Licensed CC0.

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