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The metastasis suppressor NME1 inhibits melanoma cell motility via direct transcriptional induction of the integrin beta-3 gene.
Leonard, M Kathryn; Novak, Marián; Snyder, Devin; Snow, Grace; Pamidimukkala, Nidhi; McCorkle, Joseph R; Yang, Xiuwei H; Kaetzel, David M.
Afiliación
  • Leonard MK; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland-Baltimore, Baltimore, MD, United States; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland-Baltimore, Baltimore, MD, United States.
  • Novak M; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland-Baltimore, Baltimore, MD, United States; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland-Baltimore, Baltimore, MD, United States.
  • Snyder D; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland-Baltimore, Baltimore, MD, United States; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland-Baltimore, Baltimore, MD, United States.
  • Snow G; Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland-Baltimore, Baltimore, MD, United States.
  • Pamidimukkala N; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland-Baltimore, Baltimore, MD, United States; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland-Baltimore, Baltimore, MD, United States.
  • McCorkle JR; Markey Cancer Center, Lexington, KY, United States.
  • Yang XH; Department of Pharmacology and Nutritional Sciences, University of Kentucky, College of Medicine, United States.
  • Kaetzel DM; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland-Baltimore, Baltimore, MD, United States; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland-Baltimore, Baltimore, MD, United States. Electronic address: DKaetzel@som.umaryland
Exp Cell Res ; 374(1): 85-93, 2019 01 01.
Article en En | MEDLINE | ID: mdl-30458180
Expression of the metastasis suppressor NME1 in melanoma is associated with reduced cellular motility, invasion, and metastasis, but mechanisms underlying these activities are not completely understood. Herein we report a novel mechanism through which NME1 drives formation of large, stable focal adhesions (FAs) in melanoma cells via induction of integrin ß3 (ITGß3), and in one cell line, concomitant suppression of integrin ß1 (ITGß1) transcripts. Forced expression of NME1 resulted in a strong activation of the promoter region (-301 to +13) of the ITGB3 gene. Chromatin immunoprecipitation (ChIP) analysis revealed the transcriptional induction was associated with direct recruitment of NME1 and an increase in the epigenetic activation mark, acetylation of histone 3 on lysine 27 (H3K27Ac) to a 1 kb stretch of 5'-flanking sequence of the ITGB3 gene. Unexpectedly, NME1 did not affect the amount either ITGß1 or ITGß3 proteins were internalized and recycled, processes commonly associated with regulating expression of integrins at the cell surface. The ability of NME1 to suppress motile and invasive phenotypes of melanoma cells was dependent on its induction of ITGß3. Expression of ITGß3 mRNA was associated with increased disease-free survival time in melanoma patients of the TCGA collection, consistent with its potential role as an effector of the metastasis suppressor function of NME1. Together, these data indicate metastasis suppressor activity of NME1 in melanoma is mediated by induction of ITGB3 gene transcription, with NME1-driven enrichment of ITGß3 protein at the cell membrane resulting in attenuated cell motility through the stabilization of large focal adhesions.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transcripción Genética / Movimiento Celular / Integrina beta3 / Nucleósido Difosfato Quinasas NM23 / Melanoma Límite: Animals / Humans Idioma: En Revista: Exp Cell Res Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transcripción Genética / Movimiento Celular / Integrina beta3 / Nucleósido Difosfato Quinasas NM23 / Melanoma Límite: Animals / Humans Idioma: En Revista: Exp Cell Res Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos