title: PRMT2 and RORγ expression are associated with breast cancer survival outcomes.
abstract: Protein arginine methyltransferases (PRMTs) methylate arginine residues on histones and target transcription factors that play critical roles in many cellular processes, including gene transcription, mRNA splicing, proliferation, and differentiation. Recent studies have linked PRMT-dependent epigenetic marks and modifications to carcinogenesis and metastasis in cancer. However, the role of PRMT2-dependent signaling in breast cancer remains obscure. We demonstrate PRMT2 mRNA expression was significantly decreased in breast cancer relative to normal breast. Gene expression profiling, Ingenuity and protein-protein interaction network analysis after PRMT2-short interfering RNA transfection into MCF-7 cells, revealed that PRMT2-dependent gene expression is involved in cell-cycle regulation and checkpoint control, chromosomal instability, DNA repair, and carcinogenesis. For example, PRMT2 depletion achieved the following: 1) increased p21 and decreased cyclinD1 expression in (several) breast cancer cell lines, 2) decreased cell migration, 3) induced an increase in nucleotide excision repair and homologous recombination DNA repair, and 4) increased the probability of distance metastasis free survival (DMFS). The expression of PRMT2 and retinoid-related orphan receptor-γ (RORγ) is inversely correlated in estrogen receptor-positive breast cancer and increased RORγ expression increases DMFS. Furthermore, we found decreased expression of the PRMT2-dependent signature is significantly associated with increased probability of DMFS. Finally, weighted gene coexpression network analysis demonstrated a significant correlation between PRMT2-dependent genes and cell-cycle checkpoint, kinetochore, and DNA repair circuits. Strikingly, these PRMT2-dependent circuits are correlated with pan-cancer metagene signatures associated with epithelial-mesenchymal transition and chromosomal instability. This study demonstrates the role and significant correlation between a histone methyltransferase (PRMT2)-dependent signature, RORγ, the cell-cycle regulation, DNA repair circuits, and breast cancer survival outcomes.
authors.affiliation: Institute for Molecular Bioscience (T.G.O., P.B., J.G., N.E., S.G., D.H.D., G.E.O.M.) and School of Biomedical Science (A.G.S.), The University of Queensland, Brisbane, Queensland 4072, Australia; Institute of Health and Biomedical Innovation (E.D.), Queensland University of Technology, Translational Research Institute, Brisbane, Queensland 4102, Australia; Prince Henry's Institute of Medical Research (J.W.F., P.J.F., E.R.S.), Clayton, Victoria 3168, Australia; Dame Roma Mitchell Cancer Research Laboratory (W.D.T.), School of Medicine, The University of Adelaide, Adelaide 5005, South Australia, Australia; Western Australian Institute for Medical Research (P.J.L.), University of Western Australia, Perth, Western Australia 6009, Australia; Westmead Millennium Institute (C.L.C.), Sydney Medical School, Westmead, University of Sydney, New South Wales 2006, Australia; and Department of Molecular and Clinical Medicine/Wallenberg Laboratory (G.E.O.M.), University of Gothenburg, S-405 30 Gothenburg, Sweden.
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Oh
authors.forename: Peter
authors.initials: P
authors.lastname: Bailey
authors.forename: Eloise
authors.initials: E
authors.lastname: Dray
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Smith
authors.forename: Joel
authors.initials: J
authors.lastname: Goode
authors.forename: Natalie
authors.initials: N
authors.lastname: Eriksson
authors.forename: John W
authors.initials: JW
authors.lastname: Funder
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
authors.forename: Evan R
authors.initials: ER
authors.lastname: Simpson
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Leedman
authors.forename: Christine L
authors.initials: CL
authors.lastname: Clarke
authors.forename: Sean
authors.initials: S
authors.lastname: Grimmond
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Dowhan
authors.forename: George E O
authors.initials: GE
authors.lastname: Muscat
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D018386:Kinetochores / Q000378:metabolism; D061986:MCF-7 Cells; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000096:biosynthesis / Q000235:genetics*; D060066:Protein Interaction Maps; D011484:Protein-Arginine N-Methyltransferases / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C530104:CCND1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C539900:RORC protein, human; D011960:Receptors, Estrogen; D019938:Cyclin D1; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases