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AP-2α-Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis.
White, Jeffrey R; Thompson, Dakota T; Koch, Kelsey E; Kiriazov, Boris S; Beck, Anna C; van der Heide, Dana M; Grimm, Benjamin G; Kulak, Mikhail V; Weigel, Ronald J.
Afiliación
  • White JR; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • Thompson DT; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • Koch KE; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • Kiriazov BS; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • Beck AC; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • van der Heide DM; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • Grimm BG; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • Kulak MV; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • Weigel RJ; Department of Surgery, University of Iowa, Iowa City, Iowa. ronald-weigel@uiowa.edu.
Cancer Res ; 81(17): 4455-4470, 2021 09 01.
Article en En | MEDLINE | ID: mdl-34210752
In melanoma metastasis, the role of the AP-2α transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A 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 EZH2. 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 EZH2 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 Tfap2a High/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 EZH2 through inhibition of the NuRD repression complex, serving as a biomarker to predict responsiveness to EZH2 inhibitors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complejo 2 de Proteína Adaptadora / Subunidades alfa de Complejo de Proteína Adaptadora / Factores de Transcripción E2F / Proteína Potenciadora del Homólogo Zeste 2 / Melanoma Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complejo 2 de Proteína Adaptadora / Subunidades alfa de Complejo de Proteína Adaptadora / Factores de Transcripción E2F / Proteína Potenciadora del Homólogo Zeste 2 / Melanoma Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos