Castration-resistant prostate cancer (CRPC) nearly inevitably develops after long-term treatment with androgen deprivation therapy (ADT), leading to significant mortality. Investigating the mechanisms driving CRPC development is imperative. Here, we determined that the pioneer transcription factor GATA2, which is frequently amplified in CRPC patients, inhibits interferon (IFN)-β-mediated antitumor immunity, thereby promoting CRPC progression. Employing a genetically engineered mouse model (GEMM), we demonstrated that GATA2 overexpression hindered castration-induced cell apoptosis and tumor shrinkage, facilitating tumor metastasis and CRPC development. Notably, GATA2 drives castration resistance predominantly via repressing castration-induced activation of IFN-β signaling and CD8+ T-cell infiltration. This finding aligns with the negative correlation between GATA2 expression and IFNB1 expression, as well as CD8+ T-cell infiltration in CRPC patients. Mechanistically, GATA2 recruited PIAS1 as corepressor, and reprogramed the cistrome of IRF3, a key transcription factor of the IFN-β axis, in an androgen-independent manner. Furthermore, we identified a novel silencer element that facilitated the function of GATA2 and PIAS1 through looping to the IFNB1 promoter. Importantly, depletion of GATA2 augmented antitumor immunity and attenuated CRPC development. Consequently, our findings elucidate a novel mechanism wherein GATA2 promotes CRPC progression by suppressing IFN-β axis-mediated antitumor immunity, underscoring GATA2 as a promising therapeutic target for CRPC.
Oncogene. 2024 Jul 27 [Epub ahead of print]
Zige Jin, Hanling Wang, Ruxian Tang, Biying Pan, Hui-Ju Lee, Siqi Liu, Leiming Wang, Jun Qin, Mafei Xu
School of Life Sciences, Anhui Medical University, Hefei, Anhui, China., CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China., Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Center for Translational Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China., CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. ., School of Life Sciences, Anhui Medical University, Hefei, Anhui, China. .