Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis
Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis
复制标题
染色质重塑因子 ARID2 通过 DNMT1-Snail 轴抑制肝细胞癌转移
DOI：
10.1073/pnas.1914937117
复制
发表时间：
2020-03-03
影响因子：
11.1
通讯作者：
Xie, Dong
中科院分区：
文献类型：
--
作者：
Jiang, Hao;Cao, Hui-Jun;Xie, Dong
本研究发现ARID 2的表达与HCC的转移呈负相关，与HCC患者的预后呈正相关。我们证明ARID 2通过将DNMT 1募集到Snail的启动子来抑制HCC细胞的转移，这提高了DNA甲基化并抑制了Snail转录。值得注意的是，我们在转移性HCC组织中发现了C2 H2截短突变（3817 C> T）。我们进一步揭示了C2 H2结构域是ARID 2-DNMT 1相互作用所必需的，并且发现具有破坏的C2 H2结构域的ARID 2功能丧失突变体与HCC转移和HCC患者的不良生存率正相关。总之，我们的研究不仅扩大了对ARID 2及其突变在HCC中的全面了解，而且为ARID 2缺陷型HCC的治疗提供了指征。复发和转移仍然是肝细胞癌（HCC）成功治疗的主要障碍。染色质重塑因子ARID 2在HCC中常见突变，表明其在癌症发展中的重要作用。然而，其在HCC转移中的作用在很大程度上是难以捉摸的。在本研究中，我们发现ARID 2在转移性HCC组织中的表达显著降低，与病理分级、器官转移呈负相关，与HCC患者的生存呈正相关。ARID 2在体外抑制HCC细胞的迁移和侵袭，在体内抑制转移。此外，ARID 2敲除促进不同HCC小鼠模型中的肺转移。机制研究表明，ARID 2通过将DNMT 1募集到Snail启动子，从而增加启动子甲基化并抑制Snail转录，从而抑制HCC细胞的上皮-间质转化（EMT）。此外，我们发现C2 H2结构域被破坏的ARID 2突变体失去了转移抑制功能，与HCC转移和预后不良呈正相关。总之，我们的研究揭示了ARID 2在HCC中的转移抑制作用以及潜在的机制，并为ARID 2缺陷型HCC提供了潜在的治疗靶点。
Significance In this study, we find that ARID2 expression is negatively correlated with HCC metastasis and positively associated with prognosis of HCC patients. We demonstrate that ARID2 inhibits metastasis of HCC cells by recruiting DNMT1 to the promoter of Snail, which elevates DNA methylation and suppresses Snail transcription. Notably, we discover a C2H2 truncated mutation (3817C > T) in metastatic HCC tissue. We further reveal that C2H2 domain is required for ARID2–DNMT1 interaction and find loss-of-function ARID2 mutants with disrupted C2H2 domain are positively associated with HCC metastasis and poor survival of HCC patients. Taken together, our study not only expands comprehensive understanding of ARID2 and its mutations in HCC, but also provides indication for treatment of ARID2-deficient HCC. Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial–mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.