# Defining and targeting the epigenetic programs involved in melanoma development

> **NIH NIH R21** · H. LEE MOFFITT CANCER CTR & RES INST · 2022 · $236,321

## Abstract

Project summary
Ultraviolet radiation (UVR) exposure has long been linked to melanoma development, with clear correlations
seen between latitude and the incidence of melanoma, particularly in individuals with fair skin and a poor ability
to tan. As such, sporadic cutaneous melanoma has one of the highest mutational burdens of all cancers. The
high mutational burden following UVR exposure is associated with increased neoantigen load and greater
immune recognition. These observations suggest that the melanocytes that initiate melanoma survive UVR -
induced stress/cell damage and then avoid immune recognition. Unrelated studies in our lab focused on BRAF
inhibitor resistance in melanoma identified a stress-activated epigenetic program mediated through histone
deacetylase (HDAC)-8 that allowed escape from both cell death and immune recognition through
transcriptional reprogramming. The objective of this proposal is to develop novel melanoma prevention
strategies that target the epigenetic programs required for UVR-damaged melanocytes to avoid cell death and
immune recognition. We will test the hypothesis that UVR-induced HDAC8 activation allows melanocytes to
avoid cell death and immune attack, allowing cells with pathogenic mutations to survive and later develop into
melanoma. This proposal is conceptually innovative in seeking to define the role of HDAC8 in the epigenetic
reprogramming of melanocytes that experience UVR-induced stress and DNA damage. We will further address
the role of immune evasion in the development of melanoma precursor lesions and will use unique mouse
models, single cell RNA-Seq, and multi-Omics approaches to identify core pathways and regulators involved in
the persistence of UVR-damaged melanocytes that constitute the precursor lesions for melanoma
development. In Aim 1, we will define how HDAC8 modulates the transcriptional profile of melanocytes
following UV-irradiation and will determine how this contributes to increased cell survival and reduced
immunogenicity. We will then use our recently developed HDAC8 mouse model to demonstrate the role for
HDAC8-induction in melanoma development and will perform single cell RNA-Seq and immune profiling to
characterize how HDAC8 activation in melanocytes modulates the immune microenvironment of the skin. In
Aim 2, we will determine whether inhibition of HDAC8 using genetic silencing or small molecule HDAC8
inhibitors reverses the survival and immune escape transcriptional programs that are activated in melanocytes
following UVR exposure. In vivo studies will evaluate whether HDAC8 inhibitors or silencing of HDAC8 in
mouse skin melanocytes are sufficient to delay the initiation of melanoma development in our BRAF
mutant/PTEN-silenced melanoma model, and the role of the immune system in this response. At completion of
this work we expect to have demonstrated the proof-of-principle for the development of HDAC8 inhibitors as a
novel melanoma prevention strategy.

## Key facts

- **NIH application ID:** 10354080
- **Project number:** 1R21CA267141-01
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Keiran Smalley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $236,321
- **Award type:** 1
- **Project period:** 2022-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354080

## Citation

> US National Institutes of Health, RePORTER application 10354080, Defining and targeting the epigenetic programs involved in melanoma development (1R21CA267141-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10354080. Licensed CC0.

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