# Role of PADI4 as a key epigenetic regulator of the p53 pathway and tumor suppression

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $7,481

## Abstract

PROJECT SUMMARY
TP53 is the most frequently mutated gene in human cancer. While it is well understood that the ability of p53
to act as a transcription factor is required for tumor suppression, the key target genes downstream of p53
required for tumor suppression are still incompletely understood. Moreover, attempts at drugging p53 have
proven ineffective, generating a need to understand downstream players in the tumor suppressive pathway
to develop novel therapies. The Murphy lab has characterized three p53 variants termed “hypomorphs” that
are minimally impaired for p53 transcriptional function but have increased cancer-risk. These three p53
hypomorphs are impaired for transactivation of only a few target genes, with the top target gene impaired
being peptidyl-arginine deiminase 4 (PADI4). PADI4 is a regulator of histone modification via citrullination,
which is the process of deiminating unmodified or mono-methylated arginine to the non-natural amino acid
citrulline. Histone citrullination is predicted to regulate gene transcription and is known in some cases to
decondense chromatin. PADI4 dependent citrullination is also involved in immune cell activation and
recruitment. Previous reports have suggested PADI4 may act as an oncogene or a tumor suppressor, and
the reasons underlying this controversy remain unclear. Additionally, mechanistic studies on PADI4 and
histone citrullination in cancer are lacking. TCGA analysis reveals that PADI4 is downregulated or mutated
in multiple human cancers, including mutations in 8% of melanoma, suggesting that this gene is a tumor
suppressor. I have found that PADI4 levels increase in response to genotoxic injury in multiple tissues, but
this is abolished in p53Y107H and PADI4 KO mice. PADI4 also suppresses the proliferation of both p53 wild
type (WT) and p53-null cancer cells. RNA-seq analysis of cells treated with the p53 stabilizer Nutlin-3a, +/-
si-PADI4, reveals PADI4 to be required for transcriptional activation of a subset of p53 target genes.
Collectively, these data suggest that PADI4 as a novel epigenetic regulator in cancer and may play a key role
in p53-mediated tumor suppression. I hypothesize that PADI4 contributes to tumor suppression through
interaction with p53, and through regulating chromatin organization by citrullinating histones and
opening chromatin at targeted loci. To test this hypothesis, I propose two aims. In the first aim, I will
establish the direct transcriptional targets of PADI4 in p53 WT and p53 null melanoma cells. I will also formally
test the hypothesis that PADI4 increases histone citrullination to induce changes in chromatin accessibility.
In the second aim, I will assess the tumor suppressive ability of PADI4 and PADI4 target genes in xenograft
tumor growth studies. Finally, whereas PADI4 has a clear transcriptional role, PADI4 is also known to
enhance antigen recognition, but whether this contributes to tumor suppression is unknown. I will test this
hypothesis. In sum...

## Key facts

- **NIH application ID:** 10839291
- **Project number:** 5F31CA277953-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Alexandra Indeglia
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $7,481
- **Award type:** 5
- **Project period:** 2023-05-01 → 2024-05-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839291

## Citation

> US National Institutes of Health, RePORTER application 10839291, Role of PADI4 as a key epigenetic regulator of the p53 pathway and tumor suppression (5F31CA277953-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10839291. Licensed CC0.

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