# Regulation of repetitive elements in cancer by P53 and epigenetic mechanisms

> **NIH NIH R37** · GEORGE WASHINGTON UNIVERSITY · 2021 · $382,820

## Abstract

Despite focused research efforts, the five year survival for ovarian cancer (OC) has remained
unchanged for decades and novel therapies are urgently needed for this deadly disease. Therapies that
activate the immune system to kill cancer cells, including anti-PD-1 checkpoint blockade therapy, have shown
vigorous and durable responses, but the majority of patients, including those with OC, fail to respond. The
underlying mechanism remains unclear. Repetitive elements (REs) comprise the majority (45%) of the human
genome. In most somatic tissues, REs are silenced by DNA methylation and other epigenetic modifications to
prevent their transcription. We demonstrated that treating OC cells with DNA methylation inhibitors (DNMTis)
and histone deacetylase inhibitors (HDACis) increases immune signaling from tumors through demethylation of
REs and production of RE double-stranded RNA to activate the interferon response. This signaling recruits
CD8+ T cells to sensitize tumors to anti-PD-1 immunotherapy. REs translate proteins that can be targeted as
tumor-associated antigens. Thus RE activation both promotes interferon signaling to reverse the immune-
suppressive tumor microenvironment and presents potential tumor-specific antigens as T cell targets.
 The premise of this proposal is that P53 and epigenetic mechanisms regulate REs in cancer and thus
mutant TP53 will affect immune signaling and response to epigenetic and immune therapy. Approximately half
of all cancers have mutations in TP53, the gene encoding the P53 protein, 90% of which are “hotspot”
mutations located in the DNA binding domain. These missense mutations encode functional proteins with
reduced transcriptional activity at canonical cell cycle target genes that may also exhibit oncogenic gain of
function transcriptional activity at new targets. High grade serous OC makes up about 70% of all cases and is
characterized by nearly 100% mutant TP53. While the critical role of P53 in cell cycle regulation and apoptosis
is known, P53 regulation of REs in cancer remains poorly defined. Approximately 30% of P53 binding sites are
found in REs and our preliminary data show that P53 binds directly to REs. Further, we show that P53 hotspot
mutant cell lines treated with DNMTi/HDACi exhibit significantly increased chromatin accessibility at REs and
transcription of REs compared to TP53 wild type cell lines. We hypothesize that mutant P53 aberrantly
activates REs, amplifying the RE-induced immune response.
 We will test this hypothesis via the following aims: In Aim 1, we will determine how wild type and mutant
TP53 regulate REs to affect the DNMTi/HDACi-induced interferon response. In Aim 2, we will determine how
p53 status affects the DNMTi/HDACi-induced T cell response and sensitization to immune therapy in a mouse
model of OC and a clinical trial of OC patients treated with immunotherapy. In Aim 3, we will evaluate REs as
tumor antigens in different P53 backgrounds. Results of this innovative work will...

## Key facts

- **NIH application ID:** 10211014
- **Project number:** 1R37CA251270-01A1
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Katherine B Chiappinelli
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,820
- **Award type:** 1
- **Project period:** 2021-04-14 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211014

## Citation

> US National Institutes of Health, RePORTER application 10211014, Regulation of repetitive elements in cancer by P53 and epigenetic mechanisms (1R37CA251270-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10211014. Licensed CC0.

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