CXXC5 suppresses hepatocellular carcinoma by promoting TGF-β-induced cell cycle arrest and apoptosis
CXXC5 suppresses hepatocellular carcinoma by promoting TGF-β-induced cell cycle arrest and apoptosis
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CXXC5 通过促进 TGF-β 诱导的细胞周期停滞和凋亡来抑制肝细胞癌
DOI：
10.1093/jmcb/mjx042
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发表时间：
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影响因子：
5.5
通讯作者：
Ye-Guang Chen
中科院分区：
文献类型：
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作者：
Xiaohua Yan;Jingyi Wu;Quanlong Jiang;Hao Cheng;Jing-Dong J. Han;Ye-Guang Chen
逃避转化生长因子-β介导的生长抑制通常与包括肝细胞癌在内的肝脏肿瘤的发生有关。为了更好地了解转化生长因子-β在肝细胞癌发生发展中的作用和潜在的分子机制，我们进行了转录组测序，以确定转化生长因子-β的靶基因。CXXC5是CXXC型锌指结构域蛋白家族的成员，是在肝癌细胞中发现的一个新的转化生长因子-β靶基因。CXXC5基因敲除可抑制相当一部分转化生长因子-β靶基因的表达，改善转化生长因子-β诱导的肝癌细胞生长抑制或凋亡，提示CXXC5在转化生长因子-β介导的抑制肝癌进展中是必需的。对TCGA数据库的分析表明，与正常组织相比，CXXC5在大多数肝癌组织中的表达都有所降低。此外，CXXC5与组蛋白脱乙酰酶HDAC1结合并竞争其与Smad2/3的相互作用，从而取消HDAC1对转化生长因子-β信号转导的抑制作用。这些结果提示CXXC5可能通过正反馈环促进转化生长因子-β信号转导而发挥肿瘤抑制作用，并揭示了肝癌通过破坏正反馈调节来绕过转化生长因子-β介导的细胞抑制的策略。我们的发现为研究转化生长因子-β信号的调控提供了新的线索，并证明了CXXC5在肝癌发生发展中的作用。
Evading TGF-β-mediated growth inhibition is often associated with tumorigenesis in liver, including hepatocellular carcinoma (HCC). To better understand the functions and the underlying molecular mechanisms of TGF-β in HCC initiation and progression, we carried out transcriptome sequencing (RNA-Seq) to identify the target genes of TGF-β. CXXC5, a member of the CXXC-type zinc finger domain-containing protein family, was identified as a novel TGF-β target gene in Hep3B HCC cells. Knockdown of CXXC5 attenuated the expression of a substantial portion of TGF-β target genes and ameliorated TGF-β-induced growth inhibition or apoptosis of Hep3B cells, suggesting that CXXC5 is required for TGF-β-mediated inhibition of HCC progression. Analysis of the TCGA database indicated that CXXC5 expression is reduced in the majority of HCC tissue samples in comparison to that in normal tissues. Furthermore, CXXC5 associates with the histone deacetylase HDAC1 and competes its interaction with Smad2/3, thereby abolishing the inhibitory effect of HDAC1 on TGF-β signaling. These observations together suggest that CXXC5 may act as a tumor suppressor by promoting TGF-β signaling via a positive feedback loop, and reveal a strategy for HCC to bypass TGF-β-mediated cytostasis by disrupting the positive feedback regulation. Our findings shed new light on TGF-β signaling regulation and demonstrate the function of CXXC5 in HCC development.