AP-2α-Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis

Jeffrey R White; Dakota T Thompson; Kelsey E Koch; Boris S Kiriazov; Anna C Beck; Dana M van der Heide; Benjamin G Grimm; Mikhail V Kulak; Ronald J Weigel

doi:10.1158/0008-5472.CAN-21-0772

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AP-2α-Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis

Journal article

Open access

Peer reviewed

AP-2α-Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis

Jeffrey R White, Dakota T Thompson, Kelsey E Koch, Boris S Kiriazov, Anna C Beck, Dana M van der Heide, Benjamin G Grimm, Mikhail V Kulak and Ronald J Weigel

Cancer research (Chicago, Ill.), Vol.81(17), pp.4455-4470

09/01/2021

DOI: 10.1158/0008-5472.CAN-21-0772

PMCID: PMC8416798

PMID: 34210752

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https://doi.org/10.1158/0008-5472.CAN-21-0772View

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Abstract

In melanoma metastasis, the role of the AP-2α transcription factor, which is encoded by , is controversial as some findings have suggested tumor suppressor activity while other studies have shown high expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2α facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including . A BioID screen found that AP-2α interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2α removed activating chromatin marks in the promoters of and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment with tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable antimetastatic effects, which were dependent on AP-2α. Single-cell RNA sequencing analysis of a metastatic melanoma mouse model revealed hyperexpansion of /E2F-activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2α/EZH2 pathway and suggest that AP-2α expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas. SIGNIFICANCE: AP-2α drives melanoma metastasis by upregulating E2F pathway genes including through inhibition of the NuRD repression complex, serving as a biomarker to predict responsiveness to EZH2 inhibitors.

Adaptor Protein Complex 2 - metabolism

Adaptor Protein Complex alpha Subunits - metabolism

Animals

Base Sequence

Benzamides - pharmacology

Biomarkers - metabolism

Biphenyl Compounds - pharmacology

Cell Line, Tumor

E2F Transcription Factors - metabolism

Enhancer of Zeste Homolog 2 Protein - metabolism

Epigenesis, Genetic

Humans

Melanocytes

Melanoma - metabolism

Mice

Mice, Inbred NOD

Mice, SCID

Morpholines - pharmacology

Neoplasm Metastasis

Neoplasm Transplantation

Neoplasms, Second Primary

Promoter Regions, Genetic

Pyridones - pharmacology

Single-Cell Analysis

Transcription Factor AP-2

Details

Title: Subtitle: AP-2α-Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis
Creators: Jeffrey R White - University of Iowa
Dakota T Thompson - University of Iowa
Kelsey E Koch - University of Iowa
Boris S Kiriazov - University of Iowa
Anna C Beck - University of Iowa
Dana M van der Heide - University of Iowa
Benjamin G Grimm - University of Iowa
Mikhail V Kulak - University of Iowa
Ronald J Weigel - University of Iowa
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.81(17), pp.4455-4470
DOI: 10.1158/0008-5472.CAN-21-0772
PMID: 34210752
PMCID: PMC8416798
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: P30 CA086862 / NCI NIH HHS T32 CA148062 / NCI NIH HHS R01 CA183702 / NCI NIH HHS
Language: English
Date published: 09/01/2021
Academic Unit: Molecular Physiology and Biophysics; Anatomy and Cell Biology; Surgery; Biochemistry and Molecular Biology
Record Identifier: 9984284341802771

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