Research Papers:
Epigenetic repression of phosphatidylethanolamine N-methyltransferase (PEMT) in BRCA1-mutated breast cancer
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Abstract
Da Li1, Fang-Fang Bi1, Na-Na Chen2, Ji-Min Cao3, Wu-Ping Sun4, Yi-Ming Zhou4, Chen Cao5, Chun-Yan Li6, Qing Yang1
1 Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
2 Department of Molecular Immunology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
3 Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
4 Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan
5 Department of Pathology, Chinese PLA General Hospital, Beijing, China
6 Department of Histology and Embryology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
Correspondence:
Da Li, email:
Keywords: PEMT, DNA methylation, Histone modifications, BRCA1, Breast cancer
Received: January 27, 2014 Accepted:February 26, 2014 Published: February 27, 2014
Abstract
Phosphatidylethanolamine N-methyltransferase (PEMT) plays a critical role in breast cancer progression. However, the epigenetic mechanism regulating PEMT transcription remains largely unknown. Here, we show that the first promoter-specific transcript 1 is the major PEMT mRNA species, and methylation of the -132 site is a key regulatory element for the PEMT gene in BRCA1-mutated breast cancer. Mechanistically, hypermethylated -132 site-mediated loss of active histone marks H3K9ac and increase of repressive histone marks H3K9me enrichment synergistically inhibited PEMT transcription. Clinicopathological data indicated that a hypermethylated -132 site was associated with histological grade (P = 0.031) and estrogen receptor status (P = 0.004); univariate survival and multivariate analyses demonstrated that lymph node metastasis was an independent and reliable prognostic factor for BRCA1-mutated breast cancer patients. Our findings imply that genetic (e.g., BRCA1 mutation) and epigenetic mechanisms (e.g., DNA methylation and histone modifications) are jointly involved in the malignant progression of PEMT-related breast cancer.
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