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: Tae Gyu Oh, Peter Bailey, Eloise Dray, Aaron G Smith, Joel Goode, Natalie Eriksson, John W Funder, Peter J Fuller, Evan R Simpson, Wayne D Tilley, Peter J Leedman, Christine L Clarke, Sean Grimmond, Dennis H Dowhan, George E O Muscat
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 28 Issue 7 Pg. 1166-85 (Jul 2014) ISSN: 1944-9917 [Electronic] United States
• PMID: 24911119 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCND1 protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Intracellular Signaling Peptides and Proteins
• Nuclear Receptor Subfamily 1, Group F, Member 3
• RNA, Messenger
• RNA, Small Interfering
• RORC protein, human
• Receptors, Estrogen
• Cyclin D1
• PRMT2 protein, human
• Protein-Arginine N-Methyltransferases

Topics

• Breast Neoplasms (genetics, mortality)
• Cell Cycle Checkpoints (genetics)
• Cell Line, Tumor
• Cell Movement (genetics)
• Chromosomal Instability (genetics)
• Cyclin D1 (biosynthesis)
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis)
• DNA Breaks, Double-Stranded
• DNA Repair (genetics)
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Intracellular Signaling Peptides and Proteins (biosynthesis, genetics)
• Kinetochores (metabolism)
• MCF-7 Cells
• Nuclear Receptor Subfamily 1, Group F, Member 3 (biosynthesis, genetics)
• Protein Interaction Maps
• Protein-Arginine N-Methyltransferases (biosynthesis, genetics)
• RNA Interference
• RNA, Messenger (biosynthesis)
• RNA, Small Interfering
• Receptors, Estrogen (metabolism)
• Signal Transduction