HDAC-4 regulates claudin-2 expression in EGFR-ERK1/2 dependent manner to regulate colonic epithelial cell differentiation.
HDAC-4 regulates claudin-2 expression in EGFR-ERK1/2 dependent manner to regulate colonic epithelial cell differentiation.
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DOI：
10.18632/oncotarget.21190
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发表时间：
2017-10-20
期刊：
影响因子：
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通讯作者：
Singh AB
中科院分区：
文献类型：
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作者：
Ahmad R;Kumar B;Pan K;Dhawan P;Singh AB
在正常结肠中，claudin-2表达仅限于含有未分化和增殖的结肠细胞的隐窝底部。紧密连接蛋白-2的表达也在结直肠癌（CRC）中上调并促进癌发生。然而，在CRC期间由增加的密蛋白-2表达调节的细胞机制和调节这种增加的机制仍然知之甚少。表观遗传机制有助于调节癌症相关基因的表达，抑制组蛋白脱乙酰酶（HDAC）诱导细胞周期停滞和分化。因此，基于全面的体外和体内分析，我们在此报告组蛋白去乙酰化酶调节claudin-2表达与结肠细胞去分化的因果关系，以促进CRC。使用结肠癌细胞的详细分化分析表明claudin-2表达和上皮分化之间的负相关。遗传操作研究揭示了HDAC-4在此过程中调节claudin-2表达的因果作用。进一步的分析确定转录调节为潜在机制，其依赖于EGFR-ERK 1/2信号的HDAC-4依赖性调节。因此，结肠肿瘤显示HDAC-4/ERK 1/2/Claudin-2信号传导的显著上调。总之，我们证明了HDAC-4/EGFR/ERK 1/2信号在调节claudin-2表达以调节结肠细胞分化中的新作用。这些发现具有临床意义，并强调了表观遗传调节作为在包括CRC在内的粘膜病理过程中调节claudin-2表达的潜在机制。
In normal colon, claudin-2 expression is restricted to the crypt bottom containing the undifferentiated and proliferative colonocytes. Claudin-2 expression is also upregulated in colorectal cancer (CRC) and promotes carcinogenesis. However, cellular mechanism/s regulated by increased claudin-2 expression during the CRC and mechanism/s regulating this increase remain poorly understood. Epigenetic mechanisms help regulate expression of cancer-associated genes and inhibition of Histone Deacetylases (HDACs) induces cell cycle arrest and differentiation. Accordingly, based on a comprehensive in vitro and in vivo analysis we here report that Histone Deacetylases regulate claudin-2 expression in causal association with colonocyte dedifferentiation to promote CRC. Detailed differentiation analyses using colon cancer cells demonstrated inverse association between claudin-2 expression and epithelial differentiation. Genetic manipulation studies revealed the causal role of HDAC-4 in regulating claudin-2 expression during this process. Further analysis identified transcriptional regulation as the underlying mechanism, which was dependent on HDAC-4 dependent modulation of the EGFR-ERK1/2 signaling. Accordingly, colon tumors demonstrated marked upregulation of the HDAC-4/ERK1/2/Claudin-2 signaling. Taken together, we demonstrate a novel role for HDAC-4/EGFR/ERK1/2 signaling in regulating claudin-2 expression to modulate colonocyte differentiation. These findings are of clinical significance and highlight epigenetic regulation as potential mechanism to regulate claudin-2 expression during mucosal pathologies including CRC.