PRMT2 and RORλ expression are associated with breast cancer survival outcomes

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

Research output: Contribution to journalArticleResearchpeer-review

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 retinoidrelated orphan receptor-λ (RORλ) is inversely correlated in estrogen receptor-positive breast cancer and increased RORλ 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, RORλ, the cell-cycle regulation, DNA repair circuits, and breast cancer survival outcomes.

Original languageEnglish
Pages (from-to)1166-1185
Number of pages20
JournalMolecular Endocrinology
Volume28
Issue number7
DOIs
Publication statusPublished - 2014
Externally publishedYes

Cite this

Oh, T. G., Bailey, P., Dray, E., Smith, A. G., Goode, J., Eriksson, N., ... Muscat, G. E. O. (2014). PRMT2 and RORλ expression are associated with breast cancer survival outcomes. Molecular Endocrinology, 28(7), 1166-1185. https://doi.org/10.1210/me.2013-1403
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. / PRMT2 and RORλ expression are associated with breast cancer survival outcomes. In: Molecular Endocrinology. 2014 ; Vol. 28, No. 7. pp. 1166-1185.
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title = "PRMT2 and RORλ 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 retinoidrelated orphan receptor-λ (RORλ) is inversely correlated in estrogen receptor-positive breast cancer and increased RORλ 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, RORλ, the cell-cycle regulation, DNA repair circuits, and breast cancer survival outcomes.",
author = "Oh, {Tae Gyu} and Peter Bailey and Eloise Dray and Smith, {Aaron G.} and Joel Goode and Natalie Eriksson and Funder, {John W.} and Fuller, {Peter J.} and Simpson, {Evan R.} and Tilley, {Wayne D.} and Leedman, {Peter J.} and Clarke, {Christine L.} and Sean Grimmond and Dowhan, {Dennis H.} and Muscat, {George E O}",
year = "2014",
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pages = "1166--1185",
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Oh, TG, Bailey, P, Dray, E, Smith, AG, Goode, J, Eriksson, N, Funder, JW, Fuller, PJ, Simpson, ER, Tilley, WD, Leedman, PJ, Clarke, CL, Grimmond, S, Dowhan, DH & Muscat, GEO 2014, 'PRMT2 and RORλ expression are associated with breast cancer survival outcomes' Molecular Endocrinology, vol. 28, no. 7, pp. 1166-1185. https://doi.org/10.1210/me.2013-1403

PRMT2 and RORλ expression are associated with breast cancer survival outcomes. / 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.

In: Molecular Endocrinology, Vol. 28, No. 7, 2014, p. 1166-1185.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - PRMT2 and RORλ expression are associated with breast cancer survival outcomes

AU - Oh, Tae Gyu

AU - Bailey, Peter

AU - Dray, Eloise

AU - Smith, Aaron G.

AU - Goode, Joel

AU - Eriksson, Natalie

AU - Funder, John W.

AU - Fuller, Peter J.

AU - Simpson, Evan R.

AU - Tilley, Wayne D.

AU - Leedman, Peter J.

AU - Clarke, Christine L.

AU - Grimmond, Sean

AU - Dowhan, Dennis H.

AU - Muscat, George E O

PY - 2014

Y1 - 2014

N2 - 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 retinoidrelated orphan receptor-λ (RORλ) is inversely correlated in estrogen receptor-positive breast cancer and increased RORλ 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, RORλ, the cell-cycle regulation, DNA repair circuits, and breast cancer survival outcomes.

AB - 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 retinoidrelated orphan receptor-λ (RORλ) is inversely correlated in estrogen receptor-positive breast cancer and increased RORλ 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, RORλ, the cell-cycle regulation, DNA repair circuits, and breast cancer survival outcomes.

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U2 - 10.1210/me.2013-1403

DO - 10.1210/me.2013-1403

M3 - Article

VL - 28

SP - 1166

EP - 1185

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 7

ER -