Identification of Targets of Clinical FOXA1 Mutants Involved in EMT and Immune Suppression in Prostate Cancer

Its expression is elevated in advanced stages of PCa and plays a central role in oncogenic reprogramming. Recurrent coding mutations in the forkhead DNA-binding domain (FKHD) of FOXA1 become increasingly prevalent in drug-resistant metastatic PCa, particularly clustering in the Wing2 region of FKHD.

While recent studies demonstrated that these mutations promote PCa progression, the downstream targets of FKHD mutants remain poorly understood. In this study, we employed three analytical approaches to elucidate these targets: (i) traditional transcriptomic analyses, (ii) chromatin structure–based super-enhancer (SE) profiling, and (iii) immune deconvolution. We identified HPSE, an enzyme that degrades heparan sulfate, as a druggable target activated by FKHD mutants both in vitro and in vivo.