The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis.
The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis.
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DOI：
10.1002/advs.202004635
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Shen HF;Zhang WJ;Huang Y;He YH;Hu GS;Wang L;Peng BL;Yi J;Li TT;Rong R;Chen XY;Liu JY;Li WJ;Ohgi K;Li SW;Rosenfeld MG;Liu W
新的证据表明，表观遗传调节因子可以在基因转录调节和疾病发展（例如癌症）中表现出激活剂和抑制剂活性。然而，如何在特定的细胞环境中调节和协调这些双重活动仍然难以捉摸。据报道，KDM5C（一种抑制性组蛋白去甲基化酶）意外地激活雌激素受体α（ERα）靶基因，同时抑制I型干扰素（IFN）和IFN刺激基因（ISG），从而促进ERα阳性乳腺癌细胞的生长和肿瘤发生。研究发现 KDM5C 相互作用蛋白 ZMYND8 参与这两个过程。从机制上讲，KDM5C 与活性增强子结合并招募 P-TEFb 复合物来激活 ERα 靶基因，同时抑制胞浆中的 TBK1 磷酸化以抑制 I 型 IFN 和 ISG。 ERα和KDM5C的药理学抑制可有效抑制细胞生长和肿瘤发生。综上所述，表观遗传调节剂的双重激活剂和阻遏物性质共同促进了癌症的发展。一种名为 KDM5C 的组蛋白去甲基酶可激活雌激素/雌激素受体 α 靶基因以促进癌细胞生长，同时抑制 I 型干扰素和干扰素刺激基因以逃避免疫监视。 KDM5C 的双重激活剂和阻遏物性质共同促进癌症的发展。
Emerging evidence suggested that epigenetic regulators can exhibit both activator and repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in specific cellular contexts remains elusive. Here, it is reported that KDM5C, a repressive histone demethylase, unexpectedly activates estrogen receptor alpha (ERα)‐target genes, and meanwhile suppresses type I interferons (IFNs) and IFN‐stimulated genes (ISGs) to promote ERα‐positive breast cancer cell growth and tumorigenesis. KDM5C‐interacting protein, ZMYND8, is found to be involved in both processes. Mechanistically, KDM5C binds to active enhancers and recruits the P‐TEFb complex to activate ERα‐target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ERα and KDM5C is effective in inhibiting cell growth and tumorigenesis. Taken together, it is revealed that the dual activator and repressor nature of an epigenetic regulator together contributes to cancer development. A histone demethylase named KDM5C activates estrogen/estrogen receptor alpha‐target genes to promote cancer cell growth, while suppresses type I interferons and interferon‐stimulated genes to escape from immune surveillance. The dual activator and repressor nature of KDM5C together contributes to cancer development.
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