Functions And Molecular Mechanisms Of KDM5C In ER-positive Breast Cancer

The normal development,growth and survival of an organism requires varieties and multilayered precise regulation of gene expression.Once the gene expression is dysregulated,it often leads to the occurrence and development of a broad range of human diseases.Among females including Chinese women,breast cancer is the most commonly diagnosed cancer and the leading cause of death estimated by the GLOBOCAN 2018.Estrogen receptor α(ERα)-positive breast cancer,which accounts for the majority of breast cancer,is commonly treated by endocrine therapy,which targets to ERα and blocks estrogen-driven tumor growth.After longterm endocrine therapy,most of patients with ERα-positive primary tumors would develop intrinsic and acquired resistance.To overcome the limitations of endocrine resistance and eliminate cancer cells before they acquire resistance,there is urgent need to identify novel therapeutic targets and comprehensively understand the function and pathogenesis of these targets.The reversible nature of epigenetic modifications and emerging evidence supports that epigenetic modification regulators including histone demethylase have varieties functions in cancers including breast cancers,which provides unique potential therapeutic targets for us to design small molecular inhibitors for treating ERα-positive breast cancers.To determine which histone demethylases contribute to ERα-positive breast cancers,cell proliferation,ERE-based luciferase and qPCR examining estrogen(Estradiol,E2)induced genes assays were performed by knockdown each of demethylases in ERα-positive breast cancer cell line(MCF-7).In this dissertation,KDM5C was identified as a potential therapeutic target for ERαpositive breast cancers.It was required for MCF-7 cell growth and its tumorigenesis in nude mouse.Through high throughput sequencing combination with bioinformatic analysis,we found that KDM5C can be recruited to the regulatory regions of E2-induced genes where it colocalized with ERa and positively regulate genes stimulated by E2 independent of its demethylase activity.KDM5C was also found to interact with ZMYND8,which was found to co-localized with KDM5C and ERa co-bound sites and can regulate most of genes E2-induced and dependent on KDM5C.The core members of P-TEFb complex,CDK9 and Cyclin T1,were also present in KDM5C and ZMYND8 complex.The binding of CDK9 on KDM5C and ZMYND8 co-regulated E2-induced genes was dependent on KDM5C or ZMYND8,thus the Pol Ⅱ-pSer2 level on these regions was also modulated by KDM5C.Besides positively regulated E2-induced genes,KDM5C can repress genes including which can activate type Ⅰ interferon signaling and MHC class Ⅰ complex members by DAVID GO enrichment analysis of KDM5C repressed genes in basal condition.These results indicated that KDM5C can not only activate E2-induced genes,but also repress the type Ⅰ signaling pathway which has multifaceted anti-tumor immunity and can directly affect tumor cell growth and survival,and also the members of MHC class Ⅰ,thus increased the growth of ERα-positive breast cancer cells by activating E2 program and escaping immune surveillance and elimination.Therefore,by comprehensive understanding of the carcinogenic mechanisms of KDM5C will help us to develop appropriate drugs to inhibit the proliferation and survival of breast cancer cells from multifaceted pathways.