Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription in intestinal epithelial cells by reducing vitamin D receptor expression.
Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription in intestinal epithelial cells by reducing vitamin D receptor expression.
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持续活跃的 RAS 信号传导通过减少维生素 D 受体表达来减少肠上皮细胞中 1,25 二羟基维生素 D 介导的基因转录。
DOI：
10.1016/j.jsbmb.2017.01.008
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Fleet JC
中科院分区：
文献类型：
--
作者：
DeSmet ML;Fleet JC
高维生素D水平与结肠癌风险降低有关，但这些研究忽略了结肠癌分子病因的多样性。RAS激活突变在结肠癌中很常见，它们激活促增殖信号通路。我们研究了RAS激活突变对培养的结肠和肠细胞系中1，25二羟维生素D（1，25（OH）2D）介导的基因表达的影响。瞬时转染Caco-2细胞与组成型活性突变K-RAS（G12 V）显着降低1，25（OH）2D诱导的活性的人25-羟基维生素D，24羟化酶（CYP 24 A1）启动子荧光素酶和人工3X维生素D反应元件（VDRE）启动子荧光素酶报告基因。稳定表达突变型H-RAS的年轻成年小鼠结肠（YAMC）和大鼠肠上皮（RIE）细胞系抑制了1，25（OH）2D介导的CYP 24 A1 mRNA诱导。RAS效应与YAMC和RIE细胞中较低的维生素D受体（VDR）mRNA和蛋白水平相关，并且它们可以被VDR过表达部分逆转。RAS介导的VDR水平抑制不是由于VDR mRNA稳定性降低或VDR基因甲基化增加。然而，在RAS转化的YAMC细胞（YAMC-RAS）中，VDR基因近端启动子（−300 bp）、−6 kb增强子区域和外显子3增强子区域的染色质可及性显著降低。这些数据表明，组成型活性RAS信号通过减少VDR基因转录来抑制结肠上皮细胞中1，25（OH）2D介导的基因转录，但这种抑制的机制尚不清楚。这些数据表明，具有RAS激活突变的癌症可能对维生素D介导的治疗或化学预防反应较低。
High vitamin D status is associated with reduced colon cancer risk but these studies ignore the diversity in the molecular etiology of colon cancer. RAS activating mutations are common in colon cancer and they activate pro-proliferative signaling pathways. We examined the impact of RAS activating mutations on 1,25 dihydroxyvitamin D (1,25(OH)2D)-mediated gene expression in cultured colon and intestinal cell lines. Transient transfection of Caco-2 cells with a constitutively active mutant K-RAS (G12V) significantly reduced 1,25(OH)2D-induced activity of both a human 25-hydroxyvitamin D, 24 hydroxyase (CYP24A1) promoter-luciferase and an artificial 3X vitamin D response element (VDRE) promoter-luciferase reporter gene. Young Adult Mouse Colon (YAMC) and Rat Intestinal Epithelial (RIE) cell lines with stable expression of mutant H-RAS had suppressed 1,25(OH)2D-mediated induction of CYP24A1 mRNA. The RAS effects were associated with lower Vitamin D receptor (VDR) mRNA and protein levels in YAMC and RIE cells and they could be partially reversed by VDR overexpression. RAS-mediated suppression of VDR levels was not due to either reduced VDR mRNA stability or increased VDR gene methylation. However, chromatin accessibility to the VDR gene at the proximal promoter (−300 bp), an enhancer region at −6 kb, and an enhancer region located in exon 3 was significantly reduced in RAS transformed YAMC cells (YAMC-RAS). These data show that constitutively active RAS signaling suppresses 1,25(OH)2D-mediated gene transcription in colon epithelial cells by reducing VDR gene transcription but the mechanism for this suppression is not yet known. These data suggest that cancers with RAS-activating mutations may be less responsive to vitamin D mediated treatment or chemoprevention.
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