Glucose and Glutamine Deprivation Promotes Breast Cancer Lung Metastasis via BRD4‐Dependent Enhancer Activation

Vollständiger Abstract

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ABSTRACT Nutrient deprivation in the tumor microenvironment drives metastatic progression. However, its role in breast cancer metastasis and underlying epigenetic mechanisms remain unclear. We identify an enhancer‐driven transcriptional program that promotes breast cancer metastasis under nutrient deprivation. Transient glucose–glutamine deprivation in MCF7 and MDA‐MB‐231 cells induces the expression of genes involved in migration, invasion, and metastasis. Chromatin immunoprecipitation sequencing shows distinct enhancer activation, marked by increased histone H3 lysine 27 and bromodomain‐containing protein 4 (BRD4) recruitment. Targeted enhancer acetylation using dCas9–p300 increases cognate gene expression. Motif and CUT&RUN analyses indicate the enrichment and direct binding of ATF3 and c‐JUN at enhancers—essential for their activation. Transient transcriptome sequencing shows an increase in endothelin 1 ( EDN1 ) enhancer RNA (eRNA) transcription to facilitate enhancer activation, which is reduced by treatment with eRNA‐targeting antisense oligonucleotides (ASOs). In an orthotopic mouse model, BRD4 inhibition using JQ1 or MZ1 suppresses 4T1 cell metastasis. EDN1 enhancer acetylation with dCas9–p300 increases MCF7 tumor growth, which is reduced by BRD4 inhibition or ASO treatment. BRD4 and EDN1 expression is commonly upregulated in human breast metastasis. These findings define nutrient stress‐responsive enhancers as epigenetic drivers of metastatic adaptation and highlight their therapeutic potential in breast cancer.