ZNF263–NuRD-mediated repression of STAT1 curtails MHC-I antigen presentation and IFN-γ efficacy in prostate cancer
Abstract
Loss of major histocompatibility complex (MHC)-I is a hallmark of prostate cancer (PCa) immune evasion and immunotherapy failure. Here, we identify ZNF263 as a transcriptional repressor that silences MHC-I by recruiting nucleosome-remodeling and deacetylase (NuRD) to the STAT1 promoter, reducing STAT1 and MHC-I expression. Hypoxia enhances this repression through two ZNF263 modifications: phosphorylation-driven phase separation that strengthens NuRD interaction and O-GlcNAcylation at S662 that aids STAT1 promoter binding. O-GlcNAcylation also promotes interaction with protein kinase, DNA‑activated catalytic subunit (PRKDC), amplifying phosphorylation. Interferon‑gamma (IFN‑γ)‑induced MHC-I induction is augmented upon ZNF263 loss. In silico docking identified Viroptic as a Krüppel‑associated box (KRAB) pocket binder disrupting ZNF263–NuRD, derepressing STAT1, and potentiating IFN-γ antitumor immunity in vivo. High ZNF263 correlates with low MHC-I, scarce CD8+ T cells, and poor survival, providing rationale for targeting ZNF263 in PCa immunotherapy.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Han Guan
Department of Urology, Zhongda Hospital, School of Medicine, Southeast University
Likai Mao
Department of Urology, Zhongda Hospital, School of Medicine, Southeast University
Fang Fang
Tiange Wu
Department of Urology, Zhongda Hospital, School of Medicine, Southeast University
Yifei Cheng
Key Laboratory of Bio-inspired Materials and Interfacial Science, Technical Institute of Physics and Chemistry
Zonghao You
Department of Urology, Zhongda Hospital, School of Medicine, Southeast University
Hao Lin
Ruixin Zhang
Department of Urology, Zhongda Hospital, School of Medicine, Southeast University
Junyong Zhuang
Department of Urology, Zhongda Hospital, School of Medicine, Southeast University
Gao-Jun Teng
Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University
Chuanjun Shu
Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University
Shenghong Ju
Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine
Ming Chen
Wenchao Li
Department of Urology, Zhongda Hospital, School of Medicine, Southeast University
Bin Xu