MOF upregulates the estrogen receptor α signaling pathway by its acetylase activity in hepatocellular carcinoma.
MOF upregulates the estrogen receptor α signaling pathway by its acetylase activity in hepatocellular carcinoma.
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MOF 通过乙酰化酶活性上调肝细胞癌中雌激素受体 α 信号通路
DOI：
10.1111/cas.14836
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发表时间：
2021-05
期刊：
影响因子：
5.7
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Wei S;Liu W;Sun N;Wu Y;Song H;Wang C;Wang S;Zou R;Lin L;Zeng K;Zhou B;Wang M;Luan R;Yang F;Zhao Y
组蛋白乙酰转移酶MOF（KAT8）主要参与组蛋白H4在赖氨酸16（H4K16）和一些非组蛋白蛋白的乙酰化。在许多癌症中，MOF的表达水平显著降低，然而在肝细胞癌（HCC）中，MOF的生物学功能及其潜在机制仍然是不清楚的。雌激素受体α（ERα）被认为是HCC的抑癌基因。在这里，我们证明了MOF表达在HCC样品中显著降低，并且与ERα的表达正相关。MOF与ERα相互作用，参与ERα K266、K268、K299位点的乙酰化，从而抑制ERα泛素化，维持ERα的稳定性。此外，MOF参与ERα介导的反式激活的上调。MOF的消耗显著促进HCC细胞系中的细胞生长、迁移和侵袭。总之，我们的研究结果为理解MOF对HCC中ERα作用的调节机制提供了新的见解，表明MOF可能是HCC的潜在治疗靶点。总之，我们已经证明，MOF作为一个关键的组蛋白乙酰化酶参与ERα的乙酰化，从而抑制ERα的泛素化，以稳定HCC中的ERα蛋白。MOF上调ERα诱导的反式激活。MOF缺失促进HCC细胞中的细胞增殖、迁移和侵袭。
The histone acetyltransferase MOF (KAT8) is mainly involved in the acetylation of histone H4 at lysine 16 (H4K16) and some non‐histone proteins. The MOF expression level is significantly reduced in many cancers, however the biological function of MOF and its underlying mechanism are still elusive in hepatocellular carcinoma (HCC). Estrogen receptor α (ERα) has been considered as a tumor suppressor in HCC. Here, we demonstrated that MOF expression is significantly reduced in HCC samples, and is positively correlated with that of ERα. MOF interacts with ERα, and participates in acetylation of ERα at K266, K268, K299, thereby inhibiting ERα ubiquitination to maintain the stability of ERα. In addition, MOF participates in the upregulation of ERα‐mediated transactivation. Depletion of MOF significantly promotes cell growth, migration, and invasion in HCC cell lines. Taken together, our results provide new insights to understand the mechanism underlying the modulation function of MOF on ERα action in HCC, suggesting that MOF might be a potential therapeutic target for HCC. In summary, we have demonstrated that MOF as a crucial histone acetylase participates in the acetylation of ERα, thereby inhibiting the ubiquitination of ERα to stabilize ERα protein in HCC. MOF upregulates ERα‐induced transactivation. MOF depletion promotes the cell proliferation, migration, and invasion in HCC cells.