PIAS1 regulates breast tumorigenesis through selective epigenetic gene silencing

Bin Liu; Samuel Tahk; Kathleen M Yee; Randy Yang; Yonghui Yang; Ryan Mackie; Cary Hsu; Vasili Chernishof; Neil O'Brien; Yusheng Jin; Guoping Fan; Timothy F Lane; Jianyu Rao; Dennis Slamon; Ke Shuai

doi:10.1371/journal.pone.0089464

PIAS1 regulates breast tumorigenesis through selective epigenetic gene silencing

PLoS One. 2014 Feb 24;9(2):e89464. doi: 10.1371/journal.pone.0089464. eCollection 2014.

Authors

Bin Liu¹, Samuel Tahk¹, Kathleen M Yee², Randy Yang², Yonghui Yang¹, Ryan Mackie¹, Cary Hsu³, Vasili Chernishof¹, Neil O'Brien¹, Yusheng Jin⁴, Guoping Fan⁵, Timothy F Lane⁶, Jianyu Rao⁴, Dennis Slamon¹, Ke Shuai⁷

Affiliations

¹ Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
² Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California, United States of America.
³ Department of General Surgery, University of California Los Angeles, Los Angeles, California, United States of America.
⁴ Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
⁵ Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
⁶ Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, California, United States of America.
⁷ Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California, United States of America ; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California, United States of America.

Abstract

Epigenetic gene silencing by histone modifications and DNA methylation is essential for cancer development. The molecular mechanism that promotes selective epigenetic changes during tumorigenesis is not understood. We report here that the PIAS1 SUMO ligase is involved in the progression of breast tumorigenesis. Elevated PIAS1 expression was observed in breast tumor samples. PIAS1 knockdown in breast cancer cells reduced the subpopulation of tumor-initiating cells, and inhibited breast tumor growth in vivo. PIAS1 acts by delineating histone modifications and DNA methylation to silence the expression of a subset of clinically relevant genes, including breast cancer DNA methylation signature genes such as cyclin D2 and estrogen receptor, and breast tumor suppressor WNT5A. Our studies identify a novel epigenetic mechanism that regulates breast tumorigenesis through selective gene silencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast / pathology*
Breast Neoplasms / genetics*
Breast Neoplasms / pathology*
Carcinogenesis / genetics*
Cell Line, Tumor
Cyclin D2 / genetics
DNA Methylation / genetics
Epigenesis, Genetic / genetics*
Female
Gene Expression Regulation, Neoplastic / genetics
Gene Silencing
Humans
Mice, SCID
Protein Inhibitors of Activated STAT / genetics*
Proto-Oncogene Proteins / genetics
Receptors, Estrogen / genetics
Small Ubiquitin-Related Modifier Proteins / genetics*
Ubiquitin-Protein Ligases / genetics
Wnt Proteins / genetics
Wnt-5a Protein

Substances

CCND2 protein, human
Cyclin D2
PIAS1 protein, human
Protein Inhibitors of Activated STAT
Proto-Oncogene Proteins
Receptors, Estrogen
Small Ubiquitin-Related Modifier Proteins
WNT5A protein, human
Wnt Proteins
Wnt-5a Protein
Ubiquitin-Protein Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding