PRJNA799783
The role of ARID1A in the non-estrogenic modulation of IGF-1 signaling
Gaining pharmacologic access to the potential of ARID1A, a tumor suppressor protein, to mediate transcriptional control over cancer gene expression is an unresolved challenge. Retinoid X receptor ligands are pleiotropic, incompletely understood tools that regulate breast epithelial cell proliferation. We found that low-dose bexarotene (Bex) combined with the non-selective beta-blocker carvedilol (Carv) reduces proliferation of MCF10DCIS.com cells and markedly suppresses ARID1A levels. Similarly, carvedilol synergized with Bex in MCF-7 cells to suppress cell growth. ChIP-seq analysis revealed that under non-estrogenic conditions Bex+Carv alters the concerted genomic distribution of the chromatin remodeler ARID1A and acetylated histone H3K27, at sites related to insulin-like growth factor (IGF) signaling. Several distinct sites of ARID1A enrichment were identified in the IGF-1 receptor and IRS1 genes, associated with a suppression of both proteins. The knock-down of ARID1A increased IGF-1R levels, prevented IGF-1R reduction upon Bex+Carv and stimulated proliferation, while IGF-1 receptor neutralizing antibody suppressed cell growth. Our study demonstrates direct impact of ARID1A redistribution on the expression and growth regulation of IGF1-related genes, induced by repurposed clinical drugs under non-estrogenic conditions.