Hypoxia is a hallmark of aggressive prostate cancer, but how it disrupts lineage-specific transcriptional programs to drive progression remains unclear. Here, we identify the HIF1α-PHD1-FOXA1 axis as a critical mediator of hypoxic adaptation and androgen signaling suppression. Using genome-wide profiling, we demonstrate that hypoxia reprograms HIF1α chromatin occupancy, shifting its cooperation from AR to FOXA1. Mechanistically, HIF1α physically interacts with FOXA1, destabilizing it via PHD1-mediated hydroxylation—a previously unrecognized post-translational regulatory node. Under hypoxia, loss of FOXA1 attenuates androgen-responsive transcription while activating hypoxia-inducible genes, demonstrating a dual role for this axis in hypoxia adaptation and prostate cancer progression. Genetic or pharmacological disruption of HIF1α-PHD1-FOXA1 impairs prostate cancer proliferation and migration, underscoring its translational relevance. Our findings establish oxygen-dependent FOXA1 degradation as a linchpin connecting microenvironmental stress to transcriptional plasticity in advanced prostate cancer, offering new therapeutic avenues.

Hypoxia is a hallmark of aggressive prostate cancer, but how it disrupts lineage-specific transcriptional programs to drive progression remains unclear. Here, we identify the HIF1α-PHD1-FOXA1 axis as a critical mediator of hypoxic adaptation and androgen signaling suppression. Using genome-wide profiling, we demonstrate that hypoxia reprograms HIF1α chromatin occupancy, shifting its cooperation from AR to FOXA1. Mechanistically, HIF1α physically interacts with FOXA1, destabilizing it via PHD1-mediated hydroxylation—a previously unrecognized post-translational regulatory node. Loss of FOXA1 under hypoxia attenuates androgen-responsive transcription while activating hypoxia-inducible genes, revealing a dual role for this axis in metabolic adaptation and therapeutic resistance. Genetic or pharmacological disruption of HIF1α-PHD1-FOXA1 impairs prostate cancer proliferation and migration, underscoring its translational relevance. Our findings establish oxygen-dependent FOXA1 degradation as a linchpin connecting microenvironmental stress to transcriptional plasticity in advanced prostate cancer, offering new therapeutic avenues.