BRAF inhibition in melanoma is associated with the dysregulation of histone methylation and histone methyltransferases.

Autor:	Grigore F; The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA., Yang H; The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA., Hanson ND; The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA., VanBrocklin MW; Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah 84112, USA; Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah 84112, USA., Sarver AL; Masonic Cancer Center, 2231 6th St SE, Minneapolis, MN 5545, USA; Institute for Health Informatics, 420 Delaware St. SE, Minneapolis, MN 55455, USA., Robinson JP; The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA; Masonic Cancer Center, 2231 6th St SE, Minneapolis, MN 5545, USA. Electronic address: Robinsoj@umn.edu.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2020 Sep; Vol. 22 (9), pp. 376-389. Date of Electronic Publication: 2020 Jul 03.
DOI:	10.1016/j.neo.2020.06.006
Abstrakt:	The development of mutant BRAF inhibitors has improved the outcome for melanoma patients with BRAF V600E mutations. Although the initial response to these inhibitors can be dramatic, sometimes resulting in complete tumor regression, the majority of melanomas become resistant. To study resistance to BRAF inhibition, we developed a novel mouse model of melanoma using a tetracycline/doxycycline-regulated system that permits control of mutant BRAF expression. Treatment with doxycycline leads to loss of mutant BRAF expression and tumor regression, but tumors recur after a prolonged period of response to treatment. Vemurafenib, encorafenib and dabrafenib induce cell cycle arrest and apoptosis in BRAF melanoma cell lines; however, a residual population of tumor cells survive. Comparing gene expression in human cell lines and mouse tumors can assist with the identification of novel mechanisms of resistance. Accordingly, we conducted RNA sequencing analysis and immunoblotting on untreated and doxycycline-treated dormant mouse melanomas and human mutant BRAF melanoma cell lines treated with 2 μM vemurafenib for 20  days. We found conserved expression changes in histone methyltransferase genes ASH2, EZH2, PRMT5, SUV39H1, SUV39H2, and SYMD2 in P-ERK low, p-38 high melanoma cells following prolonged BRAF inhibition. Quantitative mass spectrometry, determined a corresponding reduction in histone Lys9 and Lys27 methylation and increase in Lys36 methylation in melanoma cell lines treated with 2 μM vemurafenib for 20  days. Thus, these changes as are part of the initiate response to BRAF inhibition and likely contribute to the survival of melanoma cells. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu