title: Integrated genomic and functional analyses of histone demethylases identify oncogenic KDM2A isoform in breast cancer.
abstract: Histone lysine demethylases (KDMs) comprise a large class of enzymes that catalyze site-specific demethylation of lysine residues on histones and other proteins. They play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of KDMs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of 24 KDMs in breast cancer and identified associations among recurrent copy number alterations, gene expression, breast cancer subtypes, and clinical outcome. Two KDMs, KDM2A and KDM5B, had the highest frequency of genetic amplification and overexpression. Furthermore, among the 24 KDM genes, KDM2A had the highest correlation between copy number and mRNA expression, and high mRNA levels of KDM2A were significantly associated with shorter survival of breast cancer patients. KDM2A has two isoforms: the long isoform is comprised of a JmjC domain, CXXC-zinc finger, PHD zinc finger, F-box, and the AMN1 protein domain; whereas the short isoform of KDM2A lacks the N-terminal JmjC domain but contains all other motifs. Detailed characterization of KDM2A in breast cancer revealed that the short isoform of KDM2A is more abundant than the long isoform at DNA, mRNA, and protein levels in a subset of breast cancers. Furthermore, our data indicate that the short isoform of KDM2A has oncogenic potential and functions as an oncogenic isoform in a subset of breast cancers. Taken together, our findings suggest that amplification and overexpression of the KDM2A short isoform is critical in breast cancer progression.
authors.affiliation: The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medicine, Jilin University, Jilin, China.|Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Lanxin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Andreana
authors.initials: A
authors.lastname: Holowatyj
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Zeng-Quan
authors.initials: ZQ
authors.lastname: Yang
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D044783:F-Box Proteins; D020033:Protein Isoforms; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human
keywords: KDM2A; breast cancer; copy number alteration; gene amplification; histone lysine demethylase