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GATA2 promotes castration-resistant prostate cancer development by suppressing IFN-β axis-mediated antitumor immunity

Oncogene volume 43, pages 2595–2610 (2024)Cite this article

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Abstract

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.

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Fig. 1: Overexpression of GATA2 promoted CRPC progression in PTEN-null mice.
Fig. 2: GATA2 suppressed castration-induced immune signaling in vivo.
Fig. 3: GATA2 attenuated castration-induced tumor cell apoptosis and CD8+ T-cell infiltration through blockade of IFN-β signaling.
Fig. 4: GATA2 suppressed IFNB1, IFNL2 and ISG expression in vitro.
Fig. 5: GATA2 altered the IRF3 cistrome.
Fig. 6: GATA2 recruited PIAS1 as a corepressor to control PSG expression.
Fig. 7: GATA2 and PIAS1 suppressed IFNB1 transcription through an undefined silencer element.
Fig. 8: Ablation of GATA2 suppressed CRPC progression.

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Data availability

The authors declare that all data supporting the findings of this study are available within the article and its Supplementary Information files or from the corresponding author upon reasonable request. The experimental data that support the findings of this study are available through FigShare https://doi.org/10.6084/m9.figshare.25203209. The raw sequencing data reported in this paper have been deposited in the Genome Sequence Archive (GSA) at the National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences, under accession numbers HRA004978 and CRA011658, which are publicly accessible at https://ngdc.cncb.ac.cn/gsa.

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Acknowledgements

We thank professors Ming-jer Tsai and Sophia Tsai at Baylor College of Medicine for the kind gift of GATA2OE+ mice and editorial assistance. We also thank Cheng-Tai Yu and the Genetically Engineered Mouse Core at Baylor College of Medicine for generating GATA2OE+ mice. We appreciate the technical support of the Center for Scientific Research in the School of Life Sciences, Anhui Medical University. This work was supported by a grant from the National Natural Science Foundation of China project (82073256), a talent start-up program and a research and innovation talent team from Anhui Medical University.

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  1. These authors contributed equally: Zige Jin, Hanling Wang, Ruxian Tang, Biying Pan.

Authors and Affiliations

  1. School of Life Sciences, Anhui Medical University, Hefei, Anhui, China

    Zige Jin, Ruxian Tang, Biying Pan, Siqi Liu & Mafei Xu

  2. 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

    Zige Jin, Hanling Wang & Jun Qin

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Hui-Ju Lee & Mafei Xu

  4. Center for Translational Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China

    Leiming Wang

  5. The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

    Jun Qin & Mafei Xu

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Contributions

XM and JQ conceived and designed the experimental approach and prepared the manuscript as senior authors. JZ, WH, TR and PB performed most experiments. LH and LS performed a specific subset of the experiments and analyses. WL contributed to the computational statistical analysis.

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Correspondence to Jun Qin or Mafei Xu.

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The authors declare no competing interests.

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All animal procedures were performed under a protocol (AN-1002) approved by the Institutional Animal Care and Use Committee of Baylor College of Medicine or a protocol (LLSC20200389) approved by the Institutional Animal Care and Use Committee of Anhui Medical University.

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Jin, Z., Wang, H., Tang, R. et al. GATA2 promotes castration-resistant prostate cancer development by suppressing IFN-β axis-mediated antitumor immunity. Oncogene 43, 2595–2610 (2024). https://doi.org/10.1038/s41388-024-03107-z

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