Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time-frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten(i)pe-/- mice which recapitulate prostate carcinogenesis in humans. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, which enhances malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity leading to the emergence of cells with selective Transglutaminase 2 (TGM2) expression and impaired androgen signaling. Importantly, elevated TGM2 levels in PCa patients are associated with shortened progression-free survival after prostatectomy. Finally, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention, and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy. Overall design: The aim was to determine the HIF1A cistrome in mouse prostate adenocarcinoma cells. Myc-CaP cells were treated with DMOG (HIF1A stabilizer) at a concentration of 1.0 mM for 6h. 3 samples were analyzed: 1 replicate of DMOG-treated Myc-CaP cells with 50 µg of chromatin immunoprecipitated using 5 µg of HIF1A antibody; 1 replicate of DMOG-treated Myc-CaP cells with 50 µg of chromatin immunoprecipitated using 5 µg of rabbit IgG (negative control); 1 replicate of non-immunoprecipitated chromatin (control).