# Epigenetic Control of Melanoma by MAGE Transcription Factors

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2020 · —

## Abstract

Melanoma develops as melanocytes accumulate genetic and epigenetic abnormalities, typically causing
oncogene activation and senescence, followed by escape from senescence and loss of tumor suppression.
Members of the Class I MAGE gene family are normally expressed only in developing germ cells and placenta
but their expression is activated in many malignancies including melanoma. Class I MAGE protein expression
is associated with poor clinical outcomes and resistance to treatment, and knockdown of MAGE proteins
increases melanoma cell apoptosis in vitro and decreases growth of MAGE (+) human melanoma cells in
immunocompromised mice, suggesting that MAGE proteins play important functional roles in melanoma
biology. MAGE proteins bind to and regulate KAP1, a scaffolding protein and ubiquitin E3-ligase that causes
localized chromatin compaction and represses gene expression when recruited to specific DNA sites by
KRAB-zinc finger transcription factors (KZFs), the largest group of transcription factors in vertebrates. MAGE
proteins modify KZF-KAP1 binding to and repression of specific genes, and MAGE expression affects Id1, AP2
and p16, all known to be involved in melanocytic transformation. However, the specific roles of MAGE proteins
in the biology of melanoma, their mechanisms of action, and ways to exploit them for treatment have not been
not fully characterized. Our overall goal is to understand the role of Class I MAGE expression in melanoma
development. We will test the hypothesis that MAGE proteins facilitate melanocyte transformation by
regulating expression of genes that cooperate to promote escape from senescence, and increase
melanocyte proliferation and tissue invasion.
Aim 1: To determine how MAGE affects melanocyte growth and tissue invasion.
Aim 1a will test whether MAGE promotes escape from BRAFV600E induced senescence by suppressing p16 via
Id1, using selective knockdown of endogenous Id1, p16 and MAGE in BRAFV600E (+) cells, or by ectopic
expression of BRAFV600E , Id1, p16, and MAGE, followed by measurement of cell growth and senescence
markers. Epigenetic effects of MAGE will be determined by ChIP for MAGE and histone 3 trimethylated on
leucine 9 (H3me3K9), a molecular signature of KAP1 induced gene repression.
Aim 1b will use a similar strategy to test whether MAGE regulation of AP2 promotes migration and invasion of
melanocytes in Boyden chamber and in vitro wound assays.
Aim 2: To establish in vivo associations of MAGE expression with melanocyte transformation.
This Aim will use state of the art multispectral immunohistology with a unique tissue microarray to test the
hypothesis that MAGE is expressed early in melanocyte transformation and that MAGE proteins co-localize
with markers of proliferation (Ki67) and are inversely correlated with expression of senescence markers.
Aim 3: To test the hypothesis that MAGE expression promotes melanocyte transformation in vivo.
Aim 3a will determine whether MAGE affects melanocyte migratio...

## Key facts

- **NIH application ID:** 9898234
- **Project number:** 5I01BX003315-04
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** B Jack Longley
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898234

## Citation

> US National Institutes of Health, RePORTER application 9898234, Epigenetic Control of Melanoma by MAGE Transcription Factors (5I01BX003315-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898234. Licensed CC0.

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