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 acetylationReport as inadecuate




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 - Download this document for free, or read online. Document in PDF available to download.

Molecular Cancer

, 13:26

First Online: 06 February 2014Received: 08 October 2013Accepted: 27 January 2014DOI: 10.1186-1476-4598-13-26

Cite this article as: Li, D., Bi, FF., Cao, JM. et al. Mol Cancer 2014 13: 26. doi:10.1186-1476-4598-13-26

Abstract

BackgroundDNA methyltransferase 1 DNMT1 plays a critical role in breast cancer progression. However, the epigenetic mechanism regulating DNMT1 expression remains largely unknown.

MethodsEpigenetic 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.

ResultsHypermethylated 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.

ConclusionsOur 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.

KeywordsDNMT1 Histone modifications E2F1 BRCA1 Breast cancer AbbreviationsCDCircular dichroism

CHIPChromatin immunoprecipitation

CIConfidence interval

CO-IPCo-immunoprecipitation

DNMT1DNA methyltransferase 1

E2F1E2F transcription factor 1

EREstrogen receptor

LNLymph node

MMethylated

NegNegative

PCRPolymerase chain reaction

PosPositive

PostPostmenopausal

PRProgesterone receptor

PrePremenopausal

RRRelative risk

shRNAShort hairpin RNAs

UMUnmethylated.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-26 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Author: Da Li - Fang-Fang Bi - Ji-Min Cao - Chen Cao - Bo Liu - Qing Yang

Source: https://link.springer.com/







Related documents