title: Genetic alterations of KDM4 subfamily and therapeutic effect of novel demethylase inhibitor in breast cancer.
abstract: The histone lysine demethylase KDM4 subfamily, comprised of four members (A, B, C, and D), play critical roles in controlling transcription, chromatin architecture and cellular differentiation. We previously demonstrated that KDM4C is significantly amplified and overexpressed in aggressive basal-like breast cancers and functions as a transforming oncogene. However, information regarding the genomic and transcriptomic alterations of the KDM4 subfamily in different subtypes of breast cancer remains largely incomplete. Here, we conducted a meta-analysis of KDM4A, B, C and D in breast cancer and identified associations among recurrent copy number alterations, gene expression and breast cancer subtypes. We demonstrated that KDM4A and D are also significantly overexpressed in basal-like breast cancer, whereas KDM4B overexpression is more dominant in estrogen-receptor-positive, luminal breast cancer. Next, we investigated the therapeutic potential of a novel histone demethylase inhibitor, NCDM-32B, in breast cancer. The treatment of basal breast cancer cell lines with NCDM-32B resulted in the decrease of cell viability and anchorage independent growth in soft agar. Furthermore, we found that NCDM-32B impaired several critical pathways that drive cellular proliferation and transformation in breast cancer. Our findings demonstrate genetic amplification and overexpression of the KDM4 demethylases in different subtypes of breast cancer. Furthermore, histone methylation is reversible and KDM4 demethylases are druggable targets. Thus, KDM4 inhibitors may serve as a novel therapeutic approach for a subset of aggressive breast cancer.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine Detroit, MI 48201, USA ; School of Life Science, Jiangsu Normal University Jiangsu 221116, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Oncology, Wayne State University School of Medicine Detroit, MI 48201, USA.
authors.forename: Andreana
authors.initials: A
authors.lastname: Holowatyj
authors.affiliation: Department of Oncology, Wayne State University School of Medicine Detroit, MI 48201, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Oncology, Wayne State University School of Medicine Detroit, MI 48201, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Oncology, Wayne State University School of Medicine Detroit, MI 48201, USA ; Shandong Provincial Research Institute for Family Planning Jinan, Shandong 250002, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kyoto, 606-0823, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Oncology, Wayne State University School of Medicine Detroit, MI 48201, USA ; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute Detroit, MI 48201, USA.
authors.forename: Zeng-Quan
authors.initials: ZQ
authors.lastname: Yang
keywords: GASC1; KDM4; breast cancer; gene amplification; histone demethylase