# Epigenetic control of skin homeostasis by the ULK3 nuclear kinase

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $477,112

## Abstract

SUMMARY
Field cancerization is a major clinical condition resulting from combined keratinocyte and dermal fibroblast
alterations. Identification of regulatory molecules to target alterations of both cell types is of substantial interest.
We propose that the nuclear kinase ULK3 is one such a molecule, which we previously studied for its role in
fibroblasts. Here we will pursue the following aims: (1) We will test the hypothesis that ULK3 impinges on key
transcription regulatory networks determining keratinocyte self-renewal and oncogenic potential. ULK3 is up-
regulated in keratinocyte-derived skin and head/neck Squamous Cell Carcinomas (SCCs) and silencing of the
gene suppresses proliferative and tumorigenic potential of both human keratinocytes (HKCs) and SCC cells. We
will explore the interplay between ULK3 and the p63 and GLI transcription networks in growth/differentiation of
these cells and their oncogenicity, in orthotopic models of skin cancer expansion. 2) We will test the hypothesis
that ULK3 functions at the intersection between the arginine methylome and chromatin organization. Arginine
methylation is a little investigated mode of chromatin regulation in SCCs development. We have found that ULK3
associates with the arginine methylases PRMT1 and PRMT5 (PRMTs) and that ULK3 loss in SCC cells results
in down-modulation of di-methylated forms of Histone 4 (H4R3), well established products of PRMTs activity.
We will test whether ULK3 controls PRMT1 and 5 activity and/or links these enzymes to key substrates such as
p63, GLI2 and histones (specifically H4). We will further determine whether ULK3 control of gene transcription
in HKCs and SCC involves a broader impact on chromatin organization through convergent PRMT1- and 5-
dependent mechanisms. 3) We will test the hypothesis that ULK3 is a target of translational relevance for skin
field cancerization. We will undertake a dual genetic and pharmacological approach. Genetically, we have
developed mice with Ulk3flox alleles and K14- CreER transgene for keratinocyte-specific Ulk3 deletion. We will
examine the impact of Ulk3 deletion on normal skin homeostasis and, after transfer into an albino hairless
background, assess the consequences for UVB-induced skin field cancerization. Pharmacologically, we found
that ULK3 inhibitory compounds suppress proliferative potential of SCC cells as well as cancer/stromal cell
expansion. We will extend our studies with ULK3 and PRMT1/5 inhibitors on cultured cells and further test the
most promising compounds in an in vivo orthotopic model of skin cancer/stromal cells expansion.

## Key facts

- **NIH application ID:** 10296312
- **Project number:** 1R01AR078374-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** GIAN-PAOLO DOTTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $477,112
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296312

## Citation

> US National Institutes of Health, RePORTER application 10296312, Epigenetic control of skin homeostasis by the ULK3 nuclear kinase (1R01AR078374-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10296312. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*