Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo

• Autores: Alcazar, Oscar; Achberger, Susan; Aldrich, Wayne; Hu, Zhenbo; Negrotto, Soledad; Saunthararajah, Yogen; Triozzi, Pierre
• Año de publicación: 2012
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: DECITABINE; DIFFERENTIATION; DNA METHYL TRANSFERASE 1; DNMT1; MELANOMA
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Apoptosis genes, such as TP53 and p16/CDKN2A, that mediate responses to cytotoxic chemotherapy, are frequently nonfunctional in melanoma. Differentiation may be an alternative to apoptosis for inducing melanoma cell cycle exit. Epigenetic mechanisms regulate differentiation, and DNA methylation alterations are associated with the abnormal differentiation of melanoma cells. The effects of the deoxycytidine analogue decitabine (5-aza-2'-deoxycytidine), which depletes DNA methyl transferase 1 (DNMT1), on melanoma differentiation were examined. Treatment of human and murine melanoma cells in vitro with concentrations of decitabine that did not cause apoptosis inhibited proliferation accompanied by cellular differentiation. A decrease in promoter methylation, and increase in expression of the melanocyte late-differentiation driver SOX9, was followed by increases in cyclin-dependent kinase inhibitors (CDKN) p27/CDKN1B and p21/CDKN1A that mediate cell cycle exit with differentiation. Effects were independent of the TP53, p16/CDKN2A and also the BRAF status of the melanoma cells. Resistance, when observed, was pharmacologic, characterized by diminished ability of decitabine to deplete DNMT1. Treatment of murine melanoma models in vivo with intermittent, low-dose decitabine, administered sub-cutaneously to limit high peak drug levels that cause cytotoxicity and increase exposure time for DNMT1 depletion, and with tetrahydrouridine to decrease decitabine metabolism and further increase exposure time, inhibited tumor growth and increased molecular and tumor stromal factors implicated in melanocyte differentiation. Modification of decitabine dose, schedule and formulation for differentiation rather than cytotoxic objectives inhibits the growth of melanoma cells in vitro and in vivo. Copyright © 2011 UICC.
Fil: Alcazar, Oscar. Cleveland Clinic Foundation; Estados Unidos
Fil: Achberger, Susan. Cleveland Clinic Foundation; Estados Unidos
Fil: Aldrich, Wayne. Cleveland Clinic Foundation; Estados Unidos
Fil: Hu, Zhenbo. Cleveland Clinic Foundation; Estados Unidos
Fil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cleveland Clinic Foundation; Estados Unidos
Fil: Saunthararajah, Yogen. Cleveland Clinic Foundation; Estados Unidos
Fil: Triozzi, Pierre. Cleveland Clinic Foundation; Estados Unidos