The H2A.Z-KDM1A complex promotes tumorigenesis by localizing in the nucleus to promote SFRP1 promoter methylation in cholangiocarcinoma cells.
The H2A.Z-KDM1A complex promotes tumorigenesis by localizing in the nucleus to promote SFRP1 promoter methylation in cholangiocarcinoma cells.
复制标题
DOI：
10.1186/s12885-022-10279-y
复制
发表时间：
2022-11-11
期刊：
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
--
作者：
肝内胆管细胞癌（ICC），起源于胆管，是第二个最常见的原发性肝脏恶性肿瘤，其发病率最近有所增加。H2A.Z是一种高度保守的H2 A变体，正在成为癌症中的关键调控分子。然而，其在ICC细胞中的潜在作用机制尚不清楚。在这里，我们检测了H2A.Z和SFRP 1在正常肝内胆管细胞、ICC细胞系、ICC组织微阵列和新鲜标本中的表达。分析H2 A. Z和SFRP 1表达与临床特征的关系。基于H2A.Z和SFRP 1表达分析总生存率。采用免疫沉淀法分析KDM 1A的募集，ChIP测序和BSP分析甲基化相关分子H3 K4 me 1和H3 K4 me 2在SFRP 1启动子中的富集情况，并揭示其机制。敲除和拯救实验用于确定H2A.Z和SFRP 1在体外促进肿瘤发生的潜在机制。我们发现，H2 A. Z表达的上调与ICC组织中SFRP 1表达的下调以及ICC患者的总体生存率低下有关。H2A.Z在细胞核内与KDM 1A相互作用，结合于SFRP 1启动子上游-151 ~ -136 bp区域，使其在ICC细胞中去甲基化增加。在功能上，H2A.Z沉默抑制ICC细胞的增殖和侵袭，并且这些作用通过ICC细胞中的SFRP 1沉默而减轻。我们的研究结果表明，H2A.Z抑制SFRP 1的表达，通过染色质修饰的背景下，ICC通过形成一个复杂的KDM 1A在细胞核中。在线版本包含补充材料，可在10.1186/s12885-022-10279-y获得。
Intrahepatic cholangiocarcinoma (ICC), originating from the bile ducts, is the second most common primary liver malignancy, and its incidence has recently increased. H2A.Z, a highly conserved H2A variant, is emerging as a key regulatory molecule in cancer. However, its underlying mechanism of action in ICC cells remains unclear. Here, we examined the expression of H2A.Z and SFRP1 in normal intrahepatic cholangiocytes, ICC cell lines, ICC tissue microarrays, and fresh specimens. The correlations between H2A.Z or SFRP1 expression and clinical features were analysed. The overall survival rate was analysed based on H2A.Z and SFRP1 expression. Immunoprecipitation was used to analyse the recruitment of KDM1A, and ChIP sequencing and BSP were used to analyse the enrichment of methylation-related molecules such as H3K4me1 and H3K4me2 in the SFRP1 promoter and reveal the underlying mechanisms. Knockdown and rescue experiments were used to determine the potential mechanism by which H2A.Z and SFRP1 promote tumorigenesis in vitro. We showed that upregulation of H2A.Z expression is linked to downregulation of SFRP1 expression in ICC tissues and poor overall survival in patients with ICC. H2A.Z interacted with KDM1A in the nucleus to bind to the -151 ~ -136 bp region upstream of the SFRP1 promoter to increase its demethylation in ICC cells. Functionally, H2A.Z silencing inhibited the proliferation and invasion of ICC cells, and these effects were mitigated by SFRP1 silencing in ICC cells. Our findings reveal that H2A.Z inhibits SFRP1 expression through chromatin modification in the context of ICC by forming a complex with KDM1A in the nucleus. The online version contains supplementary material available at 10.1186/s12885-022-10279-y.
登录
查看更多内容
影响因子：
4.5
作者：
Buchanan L;Durand-Dubief M;Roguev A;Sakalar C;Wilhelm B;Strålfors A;Shevchenko A;Aasland R;Shevchenko A;Ekwall K;Francis Stewart A
通讯作者：
Francis Stewart A
影响因子：
16.6
作者：
Cole L;Kurscheid S;Nekrasov M;Domaschenz R;Vera DL;Dennis JH;Tremethick DJ
通讯作者：
Tremethick DJ
影响因子：
64.5
作者：
Garcia-Bassets, Ivan;Kwon, Young-Soo;Rosenfeld, Michael G.
通讯作者：
Rosenfeld, Michael G.
影响因子：
2.9
作者：
Chu, Wen-Ting;Wang, Jin
通讯作者：
Wang, Jin
影响因子：
8.8
作者：
Domaschenz, Renae;Kurscheid, Sebastian;Tremethick, David J.
通讯作者：
Tremethick, David J.