FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Intratumoral hypoxia is linked to lethal castration-resistant prostate cancer (CRPC).
• FOXA1, an epithelial transcription factor, is downregulated in CRPC, previously shown to induce epithelial-mesenchymal transition (EMT) and cell motility.
• The direct role of FOXA1 in regulating hypoxia pathways in CRPC remains unstudied.

Purpose of the Study:

• To investigate the role of FOXA1 in regulating hypoxia transcriptional programs in prostate cancer.
• To elucidate the mechanism by which FOXA1 loss influences the tumor microenvironment and CRPC progression.
• To evaluate the therapeutic potential of targeting the identified FOXA1-HIF1A-CCL2 axis.

Main Methods:

• Correlation analysis of FOXA1 levels and hypoxia markers in clinical prostate cancer samples.
• Mechanistic studies involving direct binding of FOXA1 to HIF1A enhancer regions.
• Assessment of macrophage infiltration and cancer cell invasion in response to FOXA1 loss and HIF1A inhibition.
• Pharmacological inhibition of the HIF1A-CCL2 axis in preclinical models.

Main Results:

• FOXA1 downregulation induces hypoxia transcriptional programs in CRPC.
• FOXA1 directly binds to an enhancer of HIF1A, inhibiting its expression; HIF1A mediates FOXA1 loss-induced hypoxia.
• FOXA1 loss promotes immunosuppressive macrophage infiltration and cancer cell invasion via the HIF1A-CCL2 axis.
• Therapeutic targeting of HIF1A-CCL2 abolished FOXA1 loss-induced phenotypes.

Conclusions:

• FOXA1 plays a critical role in suppressing hypoxia and maintaining a non-permissive tumor microenvironment in prostate cancer.
• The HIF1A-CCL2 axis is a key mechanism through which FOXA1 loss drives CRPC progression.
• Targeting the HIF1A-CCL2 pathway represents a promising therapeutic strategy for CRPC with FOXA1 loss.