# Role of KMT2D and aberrant enhancers in modulating tumor microenvironment in melanoma

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $358,680

## Abstract

SUMMARY
Cancer cells acquire genetic and epigenetic alterations that increase fitness and drive progression through
multiple steps of tumor evolution. We have limited understanding of functional epigenetic events that are
associated with melanoma progression. An in vivo RNAi screen focused on epigenetic regulators identified
KMT2D, an H3K4 methyltransferase, as a tumor suppressor in melanoma. KMT2D harbors somatic mutations
in various solid and hematological malignancies including in melanoma (~15%). Consistently, loss of KMT2D in
a genetically engineered mouse model of melanoma bearing activated BRAFV600E and PTEN inactivation
drastically accelerated melanomagenesis. Human mouse melanoma tumors with KMT2D loss displayed
drastic alterations in enhancers (H3K4me1 and H3K27Ac) compared to wild type tumors and displayed poor
survival. These enhancers targeted immune modulatory genes in the tumor cells and consistently KMT2D KO
tumors showed altered tumor microenvironment. These data suggest that enhancer malfunction in melanomas
due to mutations in KMT2D may promote highly tumorigenic behavior of melanoma cells. We hypothesize that
KMT2D loss reprograms enhancers in melanoma and imparts aggressive properties to cancer cells by
misregulation of immune microenvironment. Overall objectives of this grant to understand the define roles of
KMT2D in modulating tumor microenvironment, test functionality of enhancer losses and determine molecular
mechanism of preferential enhancer regulation by KMT2D in this system.
Aim 1: To determine the mechanism of immune microenvironment alteration by KMT2D and its
mutants in melanoma.
In this aim, we will utilize iBIP;KMT2D mouse model and available human tumor data to determine alterations
in immune microenvironment in KMT2D deficient conditions.
Aim 2: To determine the functionality of immune enhancer losses in KMT2D deficient cells.
In this aim, we will perform directed tests at functionality of enhancer loss on IFNg receptors and IL11 genes by
CRISPR-Cas9 based enhancer deletion and epigenetic editing experiments.
Aim 3: To determine the molecular mechanism of KMT2D mediated regulation of immune enhancers.
Here we will perform mechanistic experiments to determine how KMT2D is recruited preferentially to immune
enhancers.
Together, our study will determine how enhancer reprogramming in tumors specifically those due to KMT2D
loss reshape the tumor microenvironment which could provide insight into new therapeutic strategies in
melanoma.

## Key facts

- **NIH application ID:** 10463568
- **Project number:** 5R01CA222214-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Kunal Rai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $358,680
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463568

## Citation

> US National Institutes of Health, RePORTER application 10463568, Role of KMT2D and aberrant enhancers in modulating tumor microenvironment in melanoma (5R01CA222214-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10463568. Licensed CC0.

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