BRCA1 affects global DNA methylation through regulation of DNMT1

Shukla, Vivek; Coumoul, Xavier; Lahusen, Tyler; Wang, Rui Hong; Xu, Xiaoling; Vassilopoulos, Athanassios; Xiao, Cuiying; Lee, Mi-Hye; Man, Yan Gao; Ouchi, Mutsuko; Ouchi, Toru; Deng, Chu Xia

doi:10.1038/cr.2010.128

Cited by 90 publications

(61 citation statements)

References 62 publications

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“…S7). Moreover, DNA methyltransferase 1 (DNMT1) plays an important role in maintaining DNA methylation patterns [25,26], Shukla showed that DNMT1 was a transcriptional target of BRCA1 [27]. Our recent study confirmed that DNMT1 mRNA and protein were decreased in BRCA1 -mutated breast cancer.…”

Section: Discussionmentioning

confidence: 52%

Epigenetic repression of phosphatidylethanolamineN-methyltransferase (PEMT) inBRCA1-mutated breast cancer

Chen

et al. 2014

Oncotarget

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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.

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Section: Discussionmentioning

confidence: 52%

Epigenetic repression of phosphatidylethanolamineN-methyltransferase (PEMT) inBRCA1-mutated breast cancer

Chen

et al. 2014

Oncotarget

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“…Sears and colleagues also showed that HBP1 inhibits the activity of Myc, a gene often overexpressed in breast cancer (27). For this study, the decreases in HBP1 associated with breast and other cancers give a framework for the reports that DNMT1 levels increase in breast cancer (64)(65)(66). Our own inspection of the public databases further added the observation that reduced HBP1 levels were statistically associated with elevated DNMT1 levels ( Fig.…”

Section: Discussionmentioning

confidence: 92%

HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence

Pan

Chen

Roth

et al. 2013

Molecular and Cellular Biology

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bThe activity of DNA methyltransferase 1 (DNMT1) is associated with diverse biological activities, including cell proliferation, senescence, and cancer development. In this study, we demonstrated that the HMG box-containing protein 1 (HBP1) transcription factor is a new repressor of DNMT1 in a complex mechanism during senescence. The DNMT1 gene contains an HBP1-binding site at bp ؊115 to ؊134 from the transcriptional start site. HBP1 repressed the endogenous DNMT1 gene through sequencespecific binding, resulting in both gene-specific (e.g., p16INK4 ) and global DNA hypomethylation changes. The HBP1-mediated repression by DNMT1 contributed to replicative and premature senescence, the latter of which could be induced by Ras and HBP1 itself. A detailed investigation unexpectedly revealed that HBP1 has dual and complex transcriptional functions, both of which contribute to premature senescence. HBP1 both repressed the DNMT1 gene and activated the p16 gene in premature senescence. The opposite transcriptional functions proceeded through different DNA sequences and differential protein acetylation. While intricate, the reciprocal partnership between HBP1 and DNMT1 has exceptional importance, since its abrogation compromises senescence and promotes tumorigenesis. Together, our results suggest that the HBP1 transcription factor orchestrates a complex regulation of key genes during cellular senescence, with an impact on overall DNA methylation state. Epigenetic alterations have essential roles in determining gene expression patterns and in setting the environment for activators or repressors to function appropriately. DNA methylation has been associated with cancer and senescence (1-4). Cellular senescence is characterized by a permanent cell cycle arrest and the acquisition of distinct morphological, physiological, and epigenetic changes in response to events such as telomere attrition, aberrant oncogene activation, or abrogation of tumor suppressor gene functions. Senescence is a tumor-suppressive process the abrogation of which enables the path to tumorigenesis (5-8). Although seemingly two distinct phenomena, cellular senescence and cancer share similarly altered global epigenetic profiles comprising complex changes in DNA methylation, involving both hypomethylation and hypermethylation of certain genes and sequences. The establishment of DNA methylation during DNA replication and DNA repair is catalyzed by a family of DNA methyltransferases (e.g., DNMT1, DNMT3A, and DNMT3B). In particular, DNMT1 mRNA expression is significantly elevated in different cancers and is regarded as a maintenance methylase (9-11). In senescence, the levels of DNA methylation and DNMT1 protein decline in concert with aging (12-15). Yet, the mechanism of age-dependent DNA methylation changes remains unknown. In this study, we found an unexpected connection to the HBP1 transcription factor, which our previous studies had linked to premature senescence (16).HBP1 is a member of the sequence-specific high-mobilitygroup (HMG) family of transcript...

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“…9 A recent study revealed that impaired function of BRCA1 leads to global DNA hypomethylation, loss of genomic imprinting, and an open chromatin configuration at premalignant stages of several types of tissues in a BRCA1 mutant mouse model and that in human clinical samples reduced expression of BRCA1 correlates with decreased levels of DNMT1 and reduced methylation of CpG islands. 40 Thus, BRCA1 dysfunction in BRACA1-associated hereditary breast cancers and sporadic basal-like breast cancers may be associated with lower methylation of CpG islands. 41,42 We found significantly higher methylation frequencies or levels in the promoter CpG islands of nine genes (APC, DLEC1, GSTP1, HOXA1, RASS-F1A, RUNX3, SCGB3A1, SFRP1, and TMEFF2) in the ER-positive group compared with the ERnegative group.…”

Section: Discussionmentioning

confidence: 99%

Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes

et al. 2012

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Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to breast cancer subtype, and to investigate whether the patterns of CpG island methylation in each subtype are associated with their cancer stem cell phenotype represented by CD44 þ /CD24À and ALDH1 expression. We performed MethyLight analysis of the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44/CD24 and ALDH1 immunohistochemistry in 36 luminal A, 33 luminal B, 30 luminal-HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer. The number of CpG island loci methylated differed significantly between subtypes, and was highest in the luminal-HER2 subtype and lowest in the basal-like subtype. Methylation frequencies and levels in 12 of the 15 genes differed significantly between subtypes, and the basal-like subtype had significantly lower methylation frequencies and levels in nine of the genes than the other subtypes. CD44 þ /CD24À and ALDH1 þ putative stem cell populations were most enriched in the basal-like subtype. Methylation of promoter CpG islands was significantly lower in CD44 þ /CD24-cell ( þ ) tumors than in CD44 þ /CD24-cell (À) tumors, even within the basallike subtype. ALDH1 ( þ ) tumors were also less methylated than ALDH1 (À) tumors. Our findings showed that promoter CpG island methylation was different in relation to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have distinct patterns of CpG island methylation according to molecular subtypes and these are associated with different stem cell phenotypes of the tumor.

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BRCA1 affects global DNA methylation through regulation of DNMT1

Cited by 90 publications

References 62 publications

Epigenetic repression of phosphatidylethanolamineN-methyltransferase (PEMT) inBRCA1-mutated breast cancer

Epigenetic repression of phosphatidylethanolamineN-methyltransferase (PEMT) inBRCA1-mutated breast cancer

HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence

Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes

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