A functional role for an intronic enhancer of the ZBTB16 gene in AR-mediated tumour suppression in ER+ breast cancer

ABSTRACT: The androgen receptor (AR) is a tumour suppressor in estrogen receptor-positive (ER⁺) breast cancer, repressing cell cycle genes and restraining proliferation. We previously identified ZBTB16 as a candidate AR-regulated tumour suppressor gene. Here, we validated ZBTB16 as a direct AR target and tested whether it mediates AR tumour suppressor activity. In clinical cohorts, ZBTB16 mRNA expression was reduced in breast tumours relative to normal tissue, and higher expression correlated with improved survival in ER+ disease. Androgen treatment increased ZBTB16 protein in ER+ breast cancer cell lines, but ZBTB16 knockdown or overexpression did not detectably alter AR anti-proliferative effects in the models tested. AR bound a conserved intron 3 hormone response region (HRRINT3) within the ZBTB16 locus in breast cancer models and clinical specimens, with androgen-dependent H3K27ac enrichment, consistent with an AR-responsive enhancer. HRRINT3 CRISPR/Cas9 deletion prevented AR-dependent ZBTB16 induction, impaired AR-mediated growth suppression, attenuated canonical AR target gene activation and increased baseline proliferation across breast and prostate cancer cells with upregulation of E2F targets. These findings identify HRRINT3 as a lineage-conserved enhancer contributing to AR-mediated tumour suppression across AR+ cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE322909 | GEO | 2026/08/23

REPOSITORIES: GEO