title: Mammalian lysine histone demethylase KDM2A regulates E2F1-mediated gene transcription in breast cancer cells.
abstract: It is established that histone modifications like acetylation, methylation, phosphorylation and ubiquitination affect chromatin structure and modulate gene expression. Lysine methylation/demethylation on Histone H3 and H4 is known to affect transcription and is mediated by histone methyl transferases and histone demethylases. KDM2A/JHDM1A/FBXL11 is a JmjC-containing histone demethylase that targets mono- and dimethylated Lys36 residues of Histone H3; its function in breast cancer is not fully understood. Here we show that KDM2A is strongly expressed in myoepithelial cells (MEPC) in breast cancer tissues by immunohistochemistry. Ductal cells from ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC) show positive staining for KDM2A, the expression decreases with disease progression to metastasis. Since breast MEPCs have tumor-suppressive and anti-angiogenic properties, we hypothesized that KDM2A could be contributing to some of these functions. Silencing KDM2A with small interfering RNAs demonstrated increased invasion and migration of breast cancer cells by suppressing a subset of matrix metalloproteinases (MMP-2, -9, -14 and -15), as seen by real-time PCR. HUVEC cells showed increased angiogenic tubule formation ability in the absence of KDM2A, with a concomitant increase in the expression of VEGF receptors, FLT-1 and KDR. KDM2A physically bound to both Rb and E2F1 in a cell cycle dependent manner and repressed E2F1 transcriptional activity. Chromatin immunoprecipitation (ChIP) assays revealed that KDM2A associates with E2F1-regulated proliferative promoters CDC25A and TS in early G-phase and dissociates in S-phase. Further, KDM2A could also be detected on MMP9, 14 and 15 promoters, as well as promoters of FLT1 and KDR. KDM2A could suppress E2F1-mediated induction of these promoters in transient transfection experiments. These results suggest a regulatory role for KDM2A in breast cancer cell invasion and migration, through the regulation of E2F1 function.
authors.affiliation: Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors.forename: Wasia
authors.initials: W
authors.lastname: Rizwani
authors.affiliation: Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors.forename: Courtney
authors.initials: C
authors.lastname: Schaal
authors.affiliation: Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors.forename: Sateesh
authors.initials: S
authors.lastname: Kunigal
authors.affiliation: Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors.forename: Srikumar
authors.initials: S
authors.lastname: Chellappan
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D044783:F-Box Proteins; D016160:Retinoblastoma Protein; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; C501162:FLT1 protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D020782:Matrix Metalloproteinases