title: Lysine demethylase 2A promotes stemness and angiogenesis of breast cancer by upregulating Jagged1.
abstract: Alterations of histone methylation dynamically regulated by methyltransferases and demethylases are frequently found in human cancers. Here, we showed that expression of lysine demethylase 2A (KDM2A) is markedly increased in human breast cancer and its overexpression is associated with tumor progression and poor prognosis. Knockdown of KDM2A in breast cancer cells reduced proliferation but not viability. Gene set enrichment analysis revealed that inhibition of KDM2A down-regulates angiogenic genes with concurrent reduction of Jagged1 (JAG1), NOTCH1 and HEY1 in the NOTCH signaling. Chromatin immunoprecipitation- quantitative polymerase chain reaction (ChIP-qPCR) demonstrated the binding of KDM2A to the JAG1 promoter and the increase of methylation of Lys-36 of histone H3 (H3K36) in KDM2A-depleted MDA-MB-231 cells. Tumorsphere formation was significantly reduced in KDM2A-depleted cells which could be reversed by ectopic expression of JAG1. A selective KDM2A inhibitor daminozide also decreased the number of tumorsphere and the number of CD24-/CD44hi cells. In addition, daminozide acted synergistically with cisplatin in cell killing. We identified SOX2 as a direct transcriptional target of KDM2A to promote cancer stemness. Depletion of KDM2A in MDA-MB-231 cells attenuated NOTCH activation and tube formation in co-cultured endothelial cells. Two pro-angiogenic factors JAG1 and PDGFA are key mediators for KDM2A to enhance angiogenesis. Finally, inhibition of KDM2A significantly decreased tumor growth and angiogenesis in orthotopic animal experiments. Collectively, we conclude that KDM2A functions as an oncogene in breast cancer by upregulating JAG1 to promote stemness, chemoresistance and angiogenesis.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Pathology, Chi-Mei Foundation Medical Center, Tainan 710, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan.|Department of Pathology, Show Chwan Memorial Hospital, Changhua City 500, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
authors.forename: You-Syuan
authors.initials: YS
authors.lastname: Lai
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
authors.forename: Chung-Hsing
authors.initials: CH
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
authors.forename: Shih Sheng
authors.initials: SS
authors.lastname: Jiang
authors.affiliation: Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.|Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D044783:F-Box Proteins / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D000072100:Jagged-1 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D044783:F-Box Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human
keywords: Jagged1; SOX2; angiogenesis; lysine demethylase 2A; stemness