CBX4 Suppresses Metastasis via Recruitment of HDAC3 to the Runx2 Promoter in Colorectal Carcinoma
CBX4 Suppresses Metastasis via Recruitment of HDAC3 to the Runx2 Promoter in Colorectal Carcinoma
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CBX4 通过招募 HDAC3 到 Runx2 启动子来抑制结直肠癌的转移
DOI：
10.1158/0008-5472.can-16-2100
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发表时间：
2016-12-15
期刊：
影响因子：
11.2
通讯作者：
Kang, Tiebang
中科院分区：
文献类型：
--
作者：
Wang, Xin;Li, Liping;Kang, Tiebang
多梳染色体盒（CBX）蛋白参与多梳阻遏复合物（PRC 1），介导表观遗传基因沉默，并赋予PRC 1不同的致癌或肿瘤抑制功能，在细胞类型依赖性的方式。在这项研究中，我们报告说，在大肠癌细胞迁移，侵袭和转移的抑制需要CBX 4介导的抑制Runx 2，一个关键的转录因子，促进大肠癌转移。在结直肠癌组织中，CBX 4与Runx 2表达呈负相关，高CBX 4表达和低Runx 2表达的组合与总生存率显著相关，比单独CBX 4或Runx 2表达更显著。从机制上讲，CBX 4将募集的组蛋白脱乙酰酶3（HDAC 3）维持在Runx 2启动子上，Runx 2启动子维持脱乙酰化的组蛋白H3 K27状态以抑制Runx 2表达。CBX 4的这种功能依赖于它与HDAC 3的相互作用，而不是依赖于它的SUMO E3连接酶、它的染色体结构域或PRC 1复合物。破坏CBX 4-HDAC 3相互作用消除了Runx 2抑制以及细胞迁移和侵袭的抑制。总的来说，我们的数据表明，CBX 4可能作为一个肿瘤抑制剂在结直肠癌，和稳定的CBX 4与HDAC 3的相互作用的策略可能有利于结直肠癌转移患者。(C)2016年AACR。
Polycomb chromobox (CBX) proteins participate in the polycomb repressive complex (PRC1) that mediates epigenetic gene silencing and endows PRC1 with distinct oncogenic or tumor suppressor functions in a cell-type-dependent manner. In this study, we report that inhibition of cell migration, invasion, and metastasis in colorectal carcinoma requires CBX4-mediated repression of Runx2, a key transcription factor that promotes colorectal carcinoma metastasis. CBX4 inversely correlated with Runx2 expression in colorectal carcinoma tissues, and the combination of high CBX4 expression and low Runx2 expression significantly correlated with overall survival, more so than either CBX4 or Runx2 expression alone. Mechanistically, CBX4 maintained recruited histone deacetylase 3 (HDAC3) to the Runx2 promoter, which maintained a deacetylated histone H3K27 state to suppress Runx2 expression. This function of CBX4 was dependent on its interaction with HDAC3, but not on its SUMO E3 ligase, its chromodomain, or the PRC1 complex. Disrupting the CBX4-HDAC3 interaction abolished Runx2 inhibition as well as the inhibition of cell migration and invasion. Collectively, our data show that CBX4 may act as a tumor suppressor in colorectal carcinoma, and strategies that stabilize the interaction of CBX4 with HDAC3 may benefit the colorectal carcinoma patients with metastases. (C) 2016 AACR.