The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis [ChIP-seq]

Emerging evidence suggested that epigenetic regulators can exhibit both co-activator and co-repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in cellular contexts remains elusive. Here, we reported that KDM5C, a repressive histone demethylase, is unexpectedly required for estrogen/estrogen receptor alpha (ERa)-induced gene transcriptional activation to promote cell proliferation, while it suppresses the expression of type I interferons (IFNs) and interferon-stimulated genes (ISGs) to escape from immuno-surveillance. KDM5C-interacting protein, ZMYND8, is found to be accompanied with KDM5C in regulation of both subsets of genes. Mechanistically, during estrogen/ERa-induced gene transcriptional activation, ERa interacts and recruits KDM5C/ZMYND8 to active enhancers, where ERa masks KDM5C’s demethylase activity towards H3K4me2/3, converting KDM5C from a co-repressor to a co-activator. Furthermore, KDM5C and ZMYND8 are found to recruit the P-TEFb complex in a cooperative manner to activate estrogen/ERa-target genes. In contrast, KDM5C/ZMYND8 represses type I IFNs and ISGs through directly interfering TBK1 phosphorylation in an enzymatic-dependent manner. The combinatory effects of KDM5C’s dual activities in regulation of genes involved in both cell proliferation and immuno-escape lead to breast cancer cell proliferation in vitro and xenograft growth in mice. Taken together, we revealed a mechanism by which a repressive epigenetic regulator can be converted to a co-activator under specific signal cues to regulate specific gene programs, and the dual nature as both a co-repressor and co-activator together contributes to cancer development. ChIP-seq performed in this study was designed to understand the molecular mechanisms underlying KDM5C in gene transcription regulation.

越来越多的研究证据表明，表观遗传调控因子（epigenetic regulators）在基因转录调控及癌症等疾病发生发展过程中，可同时发挥共激活因子（co-activator）与共抑制因子（co-repressor）的双重活性。然而，这类双重活性在细胞微环境中如何被调控与协同，目前仍尚不明确。本研究报道发现，KDM5C作为一种抑制型组蛋白去甲基化酶，竟意外地是雌激素/雌激素受体α（ERα）介导的基因转录激活过程所必需的，以此促进细胞增殖；同时，KDM5C还可通过抑制I型干扰素（IFNs）及干扰素刺激基因（ISGs）的表达，帮助肿瘤逃逸免疫监视。与KDM5C互作的蛋白ZMYND8，可与KDM5C协同参与这两类基因的调控。从机制上看，在雌激素/ERα介导的基因转录激活过程中，ERα会与KDM5C/ZMYND8结合并将其招募至活性增强子区域，此时ERα会遮蔽KDM5C对组蛋白H3赖氨酸4二甲基化/三甲基化（H3K4me2/3）的去甲基化活性，从而将KDM5C从共抑制因子转化为共激活因子。此外，研究还发现KDM5C与ZMYND8可通过协同方式招募P-TEFb复合物（P-TEFb complex），以激活雌激素/ERα靶基因。与之相反，KDM5C/ZMYND8则可通过酶活性依赖的方式直接干扰TBK1磷酸化（TBK1 phosphorylation），从而抑制I型IFNs及ISGs的表达。KDM5C的双重活性对细胞增殖与免疫逃逸相关基因的协同调控效应，可在体外促进乳腺癌细胞增殖，并在小鼠体内推动异种移植瘤的生长。综上，本研究揭示了一种全新的调控机制：抑制型表观遗传调控因子可在特定信号刺激下转化为共激活因子，从而调控特定的基因表达程序；其同时兼具共抑制因子与共激活因子的双重特性，共同参与了癌症的发生发展。本研究中开展的染色质免疫共沉淀测序（ChIP-seq），旨在解析KDM5C调控基因转录的分子机制。