Multi-omics dissection of FOXA1 reveals cancer-type-specific transcriptional networks and functional risk variants.

Authors

Binjie Luo, Qin Zhang, Xiayun Yang, Zenglai Tan, Longguang Qin, Yuehong Yang, Riitta Jokela, Nikolaos Giannareas, Aki Manninen, Gong-Hong Wei

Published in

iScience. Volume 29. Issue 8. Pages 117064. Aug 21, 2026. Epub Aug 06, 2026.

Abstract

FOXA1 is a pioneer transcription factor that shapes lineage-specific regulatory programs in hormone-associated cancers. Here, we integrated FOXA1 cistromes, transcriptomes, GWAS loci, expression-associated quantitative trait loci (eQTL) datasets, clinical cohorts, and functional assays to examine how FOXA1-directed transcriptional networks contribute to prostate and breast cancer biology. We identified high-confidence FOXA1 direct target genes that converge on shared oncogenic pathways while retaining cancer-type-specific regulatory modules. These FOXA1-associated transcriptional programs generated prognostic signatures that stratified patient outcomes across independent cohorts. In prostate cancer, cancer-risk variants were enriched within FOXA1 binding regions, and selected functional variants modulated FOXA1 occupancy and downstream key effector gene (TLE4, USP39, and CPNE1) expression. Functional validation supported roles for these genetically regulated targets in prostate cancer cell proliferation and migration. Together, our findings connect inherited noncoding variation, FOXA1 chromatin binding, transcriptional regulation, and tumor-associated phenotypes, providing a framework for understanding FOXA1-centered regulatory mechanisms in hormone-associated cancers.

PMID:
42602988
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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