Regulation of DNA methyltransferase 1 transcription in BRCA1-mutated breast cancer: a novel crosstalk between E2F1 motif hypermethylation and loss of histone H3 lysine 9 acetylation
Authors
Da Li, Fang-Fang Bi, Ji-Min Cao, Chen Cao, Bo Liu and Qing Yang
Institution
Shengjing Hospital
Country
China
Year
2014
Journal
Molecular Cancer
Abstract
Background: DNA methyltransferase 1 (DNMT1) plays a critical role in breast cancer progression. However, the
epigenetic mechanism regulating DNMT1 expression remains largely unknown.
Methods: Epigenetic regulation of DNMT1 was assessed in 85 invasive ductal carcinomas from BRCA1 mutation
carriers. Association between clinicopathological features and DNMT1 promoter methylation was determined using
Fisher’s exact test. Univariate analysis of survival was performed using the Kaplan-Meier method. Multivariate Cox
regression analysis was performed to identify the independent prognostic factors for overall survival.
Results: Hypermethylated E2F transcription factor 1 (E2F1) motif is a key regulatory element for the DNMT1 gene in
BRCA1-mutated breast cancer. Mechanistically, the abnormal E2F1 motif methylation-mediated loss of active histone
H3 lysine 9 acetylation (H3K9ac) and transcription factor E2F1 enrichment synergistically inhibited the transcription
of DNMT1. Clinicopathological data indicated that the hypermethylated E2F1 motif was associated with histological
grade, lymph node, Ki67 and E-cadherin status; univariate survival and multivariate analyses demonstrated that
lymph node metastasis was an independent and reliable prognostic factor for BRCA1-mutated breast cancer
patients.
Conclusions: Our findings imply that genetic (such as BRCA1 mutation) and epigenetic mechanisms (such as DNA
methylation, histone modification, transcription factor binding) are jointly involved in the malignant progression of
DNMT1-related breast cancer.
Keywords: DNMT1, Histone modifications, E2F1, BRCA1, Breast cancer