Epigenetic repression of phosphatidylethanolamine N -methyltransferase ( PEMT ) in BRCA1 -mutated breast cancer

// Da Li 1 , Fang-Fang Bi 1 , Na-Na Chen 2 , Ji-Min Cao 3 , Wu-Ping Sun 4 , Yi-Ming Zhou 4 , Chen Cao 5 , Chun-Yan Li 6 , Qing Yang 1 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.