title: Regulation of Transient Site-specific Copy Gain by MicroRNA.
abstract: Intra-tumor copy number heterogeneity is commonly observed in cancer; however, the molecular mechanisms that contribute to heterogeneity remain poorly understood. Up-regulation of the histone demethylase KDM4A promotes transient site-specific copy gain (TSSG) in cells; therefore, uncovering how KDM4A levels are controlled is important for understanding the regulation of copy number heterogeneity. Here, we demonstrate that KDM4A is regulated by hsa-mir-23a-3p, hsa-mir-23b-3p, and hsa-mir-137. Altering expression of these microRNAs (miRNAs) regulates KDM4A-dependent TSSG. miRNA inhibition promoted copy gains and increased expression of the drug-resistant oncogene CKS1B, which was further substantiated in primary breast tumors. Consistent with increased CKS1B expression, miRNA inhibition reduced breast cancer cell sensitivity to cisplatin. Our data identify these miRNAs as regulators of TSSG and copy gains of a drug resistance gene.
authors.affiliation: From the Massachusetts General Hospital Cancer Center and Departments of Medicine and.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Black
authors.affiliation: the Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Hailei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: the Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Jaegil
authors.initials: J
authors.lastname: Kim
authors.affiliation: the Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142 Pathology, Harvard Medical School, Massachusetts 02129 and.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: From the Massachusetts General Hospital Cancer Center and Departments of Medicine and jwhetstine@hms.harvard.edu.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*
chemical_list: C093090:CKS1B protein, human; C545567:MIRN137 microRNA, human; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D042846:CDC2-CDC28 Kinases
keywords: CKS1B; JMJD2A; KDM4A; TSSG; chromatin; cisplatin; drug resistance; genomic instability; histone demethylase; microRNA (miRNA)