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: Da Li, Fang-Fang Bi, Na-Na Chen, Ji-Min Cao, Wu-Ping Sun, Yi-Ming Zhou, Chen Cao, Chun-Yan Li, Qing Yang
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 5 Pg. 1315-25 (Mar 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24675476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• EHMT1 protein, human
• PEMT protein, human
• Phosphatidylethanolamine N-Methyltransferase
• Histone-Lysine N-Methyltransferase
• p300-CBP Transcription Factors
• p300-CBP-associated factor
• Carbon-Nitrogen Ligases
• holocarboxylase synthetases

Topics

• Breast Neoplasms (genetics, pathology)
• Carbon-Nitrogen Ligases (genetics)
• Carcinoma, Ductal, Breast (genetics, secondary)
• DNA Methylation
• Epigenetic Repression
• Female
• Gene Expression Regulation, Neoplastic
• Genes, BRCA1
• Histone-Lysine N-Methyltransferase (genetics)
• Histones (metabolism)
• Humans
• Kaplan-Meier Estimate
• Middle Aged
• Mutation
• Phosphatidylethanolamine N-Methyltransferase (genetics)
• Promoter Regions, Genetic
• Proportional Hazards Models
• Transcription, Genetic
• Tumor Cells, Cultured
• p300-CBP Transcription Factors (genetics)