蛋白质精氨酸甲基转移酶2（PRMT2）和维甲酸相关孤儿受体γ（RORγ）的表达与乳腺癌生存结果相关。
PRMT2 and RORγ expression are associated with breast cancer survival outcomes.
作者信息
Oh Tae Gyu, Bailey Peter, Dray Eloise, Smith Aaron G, Goode Joel, Eriksson Natalie, Funder John W, Fuller Peter J, Simpson Evan R, Tilley Wayne D, Leedman Peter J, Clarke Christine L, Grimmond Sean, Dowhan Dennis H, Muscat George E O
机构信息
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.
出版信息
Mol Endocrinol. 2014 Jul;28(7):1166-85. doi: 10.1210/me.2013-1403. Epub 2014 Jun 9.
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.
蛋白质精氨酸甲基转移酶（PRMTs）可使组蛋白上的精氨酸残基发生甲基化，并作用于在许多细胞过程中发挥关键作用的靶转录因子，这些过程包括基因转录、mRNA剪接、增殖和分化。最近的研究已将PRMT依赖性表观遗传标记和修饰与癌症的发生和转移联系起来。然而，PRMT2依赖性信号传导在乳腺癌中的作用仍不清楚。我们证明，与正常乳腺相比，PRMT2 mRNA在乳腺癌中的表达显著降低。将PRMT2短发夹RNA转染到MCF-7细胞后进行基因表达谱分析、通路分析和蛋白质-蛋白质相互作用网络分析，结果显示PRMT2依赖性基因表达参与细胞周期调控和检查点控制、染色体不稳定、DNA修复及癌症发生。例如，PRMT2缺失导致以下结果：1）在几种乳腺癌细胞系中p21增加而细胞周期蛋白D1表达降低；2）细胞迁移减少；3）诱导核苷酸切除修复和同源重组DNA修复增加；4）增加无远处转移生存期（DMFS）的概率。在雌激素受体阳性乳腺癌中，PRMT2与视黄酸相关孤儿受体γ（RORγ）的表达呈负相关，RORγ表达增加会提高DMFS。此外，我们发现PRMT2依赖性特征的表达降低与DMFS概率增加显著相关。最后，加权基因共表达网络分析表明，PRMT2依赖性基因与细胞周期检查点、动粒和DNA修复回路之间存在显著相关性。引人注目的是，这些PRMT2依赖性回路与上皮-间质转化和染色体不稳定相关的泛癌元基因特征相关。本研究证明了组蛋白甲基转移酶（PRMT2）依赖性特征、RORγ、细胞周期调控、DNA修复回路与乳腺癌生存结果之间的作用及显著相关性。
Zotero 插件