title: Epigenetic repression of phosphatidylethanolamine N-methyltransferase (PEMT) in BRCA1-mutated breast cancer.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Da
authors.initials: D
authors.lastname: Li
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Bi
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Chen
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Cao
authors.forename: Wu-Ping
authors.initials: WP
authors.lastname: Sun
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Zhou
authors.forename: Chen
authors.initials: C
authors.lastname: Cao
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019731:Carbon-Nitrogen Ligases / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000556:secondary; D019175:DNA Methylation; D063185:Epigenetic Repression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D050880:p300-CBP Transcription Factors / Q000235:genetics; D000099224:p300-CBP-Associated Factor
chemical_list: D019731:Carbon-Nitrogen Ligases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D050918:Phosphatidylethanolamine N-Methyltransferase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C455847:EHMT1 protein, human; C494489:PEMT protein, human; C023312:holocarboxylase synthetases