Intratumoral hypoxia is associated with castration-resistant prostate cancer (CRPC), a lethal disease. FOXA1 is an epithelial transcription factor that is down-regulated in CRPC. We have previously reported that FOXA1 loss induces epithelial-mesenchymal transition (EMT) and cell motility through elevated TGFβ signaling. However, whether FOXA1 directly regulates hypoxia pathways of CRPC tumors has not been previously studied. Here we report that FOXA1 down-regulation induces hypoxia transcriptional programs, and FOXA1 level is negatively correlated with hypoxia markers in clinical prostate cancer (PCa) samples. Mechanistically, FOXA1 directly binds to an intragenic enhancer of HIF1A to inhibit its expression, and HIF1A, in turn, is critical in mediating FOXA1 loss-induced hypoxia gene expression. Further, we identify CCL2, a chemokine ligand that modulates tumor microenvironment and promotes cancer progression, as a crucial target of the FOXA1-HIF1A axis. We found that FOXA1 loss leads to immunosuppressive macrophage infiltration and increased cell invasion, dependent on HIF1A expression. Critically, therapeutic targeting of HIF1A-CCL2 using pharmacological inhibitors abolishes FOXA1 loss-induced macrophage infiltration and PCa cell invasion. In summary, our study reveals an essential role of FOXA1 in controlling the hypoxic tumor microenvironment and establishes the HIF1A-CCL2 axis as one mechanism of FOXA1 loss-induced CRPC progression.
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RNA-seq data generated in this study were deposited to the NCBI GEO database under accession number GSE195571. Secure token for reviewers: oxelgsegfhotdsl
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This work was supported in part by the NIH prostate SPORE P50CA180995 (to JY), NIH R50CA211271 (to JCZ), and Prostate Cancer Foundation 2017CHAL2008 (to JY, JCZ). LB, SHP, and GG were supported in part by NIH/NCI training grant T32 CA009560.
The authors declare no competing interests.
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Wang, X., Brea, L., Lu, X. et al. FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A. Oncogene 41, 4259–4270 (2022). https://doi.org/10.1038/s41388-022-02423-6