表观遗传调控是肿瘤治疗研究的前沿阵地，组蛋白修饰是表观遗传调控基本机制之一。组蛋白修饰及其“阅读器”识别紊乱在肿瘤发生发展中发挥重要调节作用，组蛋白“阅读器”已经成为癌症表观药物研发的一类重要靶点。最近，我们发现了一类新型组蛋白“阅读器”—ZZ结构域，首次报道ZZ结构域在细胞核中和染色质上的生物学功能，为研究ZZ结构域在肿瘤中作用提供了全新的切入点。KCMF1作为一种ZZ结构域家族蛋白，通常在肿瘤组织中高表达。本课题利用生物化学、生物信息学、基因组学和表观基因组学等手段，将详细阐述新型组蛋白阅读器ZZ结构域对KCMF1的功能调控及其在肿瘤发生发展中的作用机制，首次明确ZZ结构域在肿瘤发生发展中的促进作用，为ZZ家族蛋白在肿瘤中的机制研究提供新的方向。本项目的研究，将为KMCF1蛋白ZZ结构域作为潜在肿瘤治疗的表观遗传靶点提供科学依据，为ZZ结构域抑制剂筛选和研发提供理论基础。

Epigenetic regulators are equally important targets for cancer therapy in academic as well as pharmaceutical research. As a fundamental epigenetic mechanism, posttranslational modifications on histones play an important role in modulating chromatin dynamics and accessibility of the underlying DNA, thus regulating all chromatin-associated processes, such as transcription. Importantly, histone-tail modifications and their effector molecules are often misregulated in cancer. Dysregulation of the homeostasis of histone modifications and their effector leads to developmental disorders and genetic diseases, including cancer. Recently, we reported the identification of a reader of histone H3, the ZZ-type zinc finger (ZZ) domain of ZZZ3, a subunit of the Ada-two-A-containing (ATAC) histone acetyltransferase complex, and ZZ domain of P300. This is the first report to study the nuclear and chromatin function of ZZ domain, which provides the new entry point for studying ZZ domain function in tumorigenesis. Upregulation of nuclear KCMF1 expression is evident in preneoplastic lesions and in several epithelial malignancies. In this proposal, we try to study the ZZ domain’s role in KCMF1-mediated pro-oncogenic functions in vitro and in vivo, which provides a new direction for the study of the mechanism of ZZ family protein in tumorigenesis. Epigenetic readers are attractive therapeutic targets for cancer treatment. The proposed study will provide evidence that the ZZ domain of KCMF1 is likely a potential therapeutic target for the treatment of cancers. Knowledge gained from this study will provide a basis for developing small molecules that target this regulatory domain for future drug therapies against cancer.