HOTAIRM1 suppresses Estrogen Receptor activity in breast cancer by restricting chromatin accessibility of pioneer factor FOXA1

ABSTRACT: Although a majority of breast cancers (BrCa) are Estrogen receptor-alpha (ERa)-positive, existing endocrine therapies that target ERa can lead to hormone-resistant disease. The mechanisms of how normal breast epithelium is transformed into malignant remain poorly defined, and a deeper understanding is needed to design novel therapeutics. Several epigenetic regulators including long non-coding RNAs (lncRNAs) are aberrantly expressed in BrCa, resulting in abnormal gene expression patterns and tumor growth. Here, we show that HOTAIRM1, which we previously defined as a p53-regulated lncRNA in human stem cells, acts as a tumor suppressor to counteract ERa-activity in BrCa. Global expression analyses uncovered a significant correlation between reduced HOTAIRM1 expression and poor survival of ER+ BrCa patients. Promoter DNA methylation and histone mark enrichment revealed that HOTAIRM1 is epigenetically silenced in BrCa patients and cell lines. We found that HOTAIRM1 depletion promotes, whereas exogenous HOTAIRM1 reduces survival and proliferation of BrCa cells. Guilt by association analysis in BrCa patients, combined with HOTAIRM1-dependent transcriptome profiling in BrCa cells reveal that HOTAIRM1 expression negatively correlates with proteins involved in ERa-activity and estrogen response. An unbiased profiling of HOTAIRM1-interactome show that HOTAIRM1 interacts with pioneer factor FOXA1 in ER+ BrCa cells. Further, our global ER/FOXA1 chromatin enrichment profiling in response to estrogen demonstrate increased enrichment of ER and FOXA1 to estrogen response elements (EREs) that results in significantly higher expression of ERa-targets in absence of HOTAIRM1. Thus, HOTAIRM1 suppresses ERa-activity in BrCa by restricting chromatin accessibility of pioneer factor FOXA1. To our knowledge, our results are the first to define a non-proteomic component that disrupts the activity of a pioneer factor in order to achieve tumor suppression

ORGANISM(S): Homo sapiens

PROVIDER: GSE135894 | GEO | 2023/08/15

REPOSITORIES: GEO