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ERα promotes transcription of tumor suppressor gene ApoA-I by establishing H3K27ac-enriched chromatin microenvironment in breast cancer cells.

ABSTRACT: Apolipoprotein A-I (ApoA-I), the main protein component of high-density lipoprotein (HDL), plays a pivotal role in reverse cholesterol transport (RCT). Previous studies indicated a reduction of serum ApoA-I levels in various types of cancer, suggesting ApoA-I as a potential cancer biomarker. Herein, ectopically overexpressed ApoA-I in MDA-MB-231 breast cancer cells was observed to have antitumor effects, inhibiting cell proliferation and migration. Subsequent studies on the mechanism of expression regulation revealed that estradiol (E2)/estrogen receptor α (ERα) signaling activates ApoA-I gene transcription in breast cancer cells. Mechanistically, our ChIP-seq data showed that ERα directly binds to the estrogen response element (ERE) site within the ApoA-I gene and establishes an acetylation of histone 3 lysine 27 (H3K27ac)‍-enriched chromatin microenvironment. Conversely, Fulvestrant (ICI 182780) treatment blocked ERα binding to ERE within the ApoA-I gene and downregulated the H3K27ac level on the ApoA-I gene. Treatment with p300 inhibitor also significantly decreased the ApoA-I messenger RNA (mRNA) level in MCF7 cells. Furthermore, the analysis of data from The Cancer Genome Atlas (TCGA) revealed a positive correlation between ERα and ApoA-I expression in breast cancer tissues. Taken together, our study not only revealed the antitumor potential of ApoA-I at the cellular level, but also found that ERα promotes the transcription of ApoA-I gene through direct genomic effects, and p300 may act as a co-activator of ERα in this process.

SUBMITTER: Wang B

PROVIDER: S-EPMC8669322 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Most variants associated with complex phenotypes in genome-wide association studies (GWAS) do not directly index coding changes affecting protein structure. Instead they are hypothesized to influence gene regulation, with common variants associated with disease being enriched in regulatory domains including enhancers and regions of open chromatin. There is interest, therefore, in using epigenomic annotation data to identify the specific regulatory mechanisms involved and prioritize risk variants. We quantified lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - across the genome in entorhinal cortex samples using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). H3K27ac peaks were called using high quality reads combined across all samples and formed the basis of partitioned heritability analysis using LD score regression along with publicly-available GWAS results for seven psychiatric and neurodegenerative traits. Heritability for all seven brain traits was significantly enriched in these H3K27ac peaks (enrichment ranging from 1.09-2.13) compared to regions of the genome containing other active regulatory and functional elements across multiple cell types and tissues. The strongest enrichments were for amyotrophic lateral sclerosis (ALS) (enrichment = 2.19; 95% CI = 2.12-2.27), autism (enrichment = 2.11; 95% CI = 2.05-2.16) and major depressive disorder (enrichment = 2.04; 95% CI = 1.92-2.16). Much lower enrichments were observed for 14 non-brain disorders, although we identified enrichment in cortical H3K27ac domains for body mass index (enrichment = 1.16; 95% CI = 1.13-1.19), ever smoked (enrichment = 2.07; 95% CI = 2.04-2.10), HDL (enrichment = 1.53; 95% CI = 1.45-1.62) and trigylcerides (enrichment = 1.33; 95% CI = 1.24-1.42). These results indicate that risk alleles for brain disorders are preferentially located in regions of regulatory/enhancer function in the cortex, further supporting the hypothesis that genetic variants for these phenotypes influence gene regulation in the brain.

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ERα promotes transcription of tumor suppressor gene ApoA-I by establishing H3K27ac-enriched chromatin microenvironment in breast cancer cells.

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