Modulation of Brahma expression by the mitogen-activated protein kinase/extracellular signal regulated kinase pathway is associated with changes in melanoma proliferation.
Modulation of Brahma expression by the mitogen-activated protein kinase/extracellular signal regulated kinase pathway is associated with changes in melanoma proliferation.
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丝裂原激活蛋白激酶/细胞外信号调节激酶途径对 Brahma 表达的调节与黑色素瘤增殖的变化有关。
DOI：
10.1016/j.abb.2014.07.004
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发表时间：
2014
影响因子：
3.9
通讯作者：
delaSerna,IvanaL
中科院分区：
文献类型：
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作者：
Mehrotra,Aanchal;Saladi,SrinivasVinod;Trivedi,ArchitR;Aras,Shweta;Qi,Huiling;Jayanthy,Ashika;Setaluri,Vijayasaradhi;delaSerna,IvanaL
Brahma (BRM) 和 Brahma 相关基因 1 (BRG1) 是 SWItch/蔗糖不可发酵 (SWI/SNF) 染色质重塑复合物的催化亚基。 BRM 在多种肿瘤中被表观遗传学沉默。 v-raf 鼠肉瘤病毒癌基因同源物 B1 (BRAF) 基因的突变在黑色素瘤中频繁发生，并导致丝裂原激活蛋白激酶 (MAPK)/细胞外信号调节激酶 (ERK1/2) 通路的组成型激活。我们测试了以下假设：BRM 表达受黑色素细胞和黑色素瘤细胞中致癌 BRAF 和 ERK1/2 磷酸化的调节。黑色素细胞和 BRAF 野生型黑色素瘤细胞中致癌 BRAF 的表达降低了 BRM 表达并增加了 BRG1 表达。在含有致癌 BRAF 的黑色素瘤细胞中，抑制丝裂原激活蛋白/细胞外信号调节激酶激酶 (MEK) 或选择性抑制 BRAF 可增加 BRM 表达并减少 BRG1 表达。 BRM 表达增加与 BRM 启动子上组蛋白乙酰化增加相关。在含有致癌 BRAF 的黑色素瘤细胞中，BRM 的过度表达促进了细胞周期进程和细胞凋亡的变化，这与肿瘤抑制作用一致。用 PLX4032 抑制 BRAF(V600E) 后，BRM 促进存活。 PLX4032 诱导的 BRM 功能变化与 BRM 蛋白乙酰化增加相关。这项研究通过调节 SWI/SNF 亚基表达和功能，深入了解黑色素瘤中致癌 BRAF 的表观遗传后果。
Brahma (BRM) and Brahma-related gene 1(BRG1) are catalytic subunits of SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes. BRM is epigenetically silenced in a wide-range of tumors. Mutations in the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene occur frequently in melanoma and lead to constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK1/2) pathway. We tested the hypothesis that BRM expression is modulated by oncogenic BRAF and phosphorylation of ERK1/2 in melanocytes and melanoma cells. Expression of oncogenic BRAF in melanocytes and melanoma cells that are wild-type for BRAF decreased BRM expression and increased BRG1 expression. Inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) or selective inhibition of BRAF in melanoma cells that harbor oncogenic BRAF increased BRM expression and decreased BRG1 expression. Increased BRM expression was associated with increased histone acetylation on the BRM promoter. Over-expression of BRM in melanoma cells that harbor oncogenic BRAF promoted changes in cell cycle progression and apoptosis consistent with a tumor suppressive role. Upon inhibition of BRAF(V600E) with PLX4032, BRM promoted survival. PLX4032 induced changes in BRM function were correlated with increased acetylation of the BRM protein. This study provides insights into the epigenetic consequences of inhibiting oncogenic BRAF in melanoma through modulation of SWI/SNF subunit expression and function.