RAD21 amplification epigenetically suppresses interferon signaling to promote immune evasion in ovarian cancer
Peng Deng, … , Xiaojun Xia, Jing Tan
Peng Deng, … , Xiaojun Xia, Jing Tan
Published October 6, 2022
Citation Information: J Clin Invest. 2022;132(22):e159628. https://doi.org/10.1172/JCI159628.
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Research Article Immunology Oncology

RAD21 amplification epigenetically suppresses interferon signaling to promote immune evasion in ovarian cancer

Abstract

Prevalent copy number alteration is the most prominent genetic characteristic associated with ovarian cancer (OV) development, but its role in immune evasion has not been fully elucidated. In this study, we identified RAD21, a key component of the cohesin complex, as a frequently amplified oncogene that could modulate immune response in OV. Through interrogating the RAD21-regulated transcriptional program, we found that RAD21 directly interacts with YAP/TEAD4 transcriptional corepressors and recruits the NuRD complex to suppress interferon (IFN) signaling. In multiple clinical cohorts, RAD21 overexpression is inversely correlated with IFN signature gene expression in OV. We further demonstrated in murine syngeneic tumor models that RAD21 ablation potentiated anti–PD-1 efficacy with increased intratumoral CD8+ T cell effector activity. Our study identifies a RAD21–YAP/TEAD4–NuRD corepressor complex in immune modulation, and thus provides a potential target and biomarker for precision immunotherapy in OV.

Authors

Peng Deng, Zining Wang, Jinghong Chen, Shini Liu, Xiaosai Yao, Shaoyan Liu, Lizhen Liu, Zhaoliang Yu, Yulin Huang, Zhongtang Xiong, Rong Xiao, Jiuping Gao, Weiting Liang, Jieping Chen, Hui Liu, Jing Han Hong, Jason Yongsheng Chan, Peiyong Guan, Jianfeng Chen, Yali Wang, Jiaxin Yin, Jundong Li, Min Zheng, Chao Zhang, Penghui Zhou, Tiebang Kang, Bin Tean Teh, Qiang Yu, Zhixiang Zuo, Qingping Jiang, Jihong Liu, Ying Xiong, Xiaojun Xia, Jing Tan

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Figure 3

RAD21 directly interacts with YAP/TEAD4 transcriptional corepressor complex to coordinately suppress ISGs.

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RAD21 directly interacts with YAP/TEAD4 transcriptional corepressor comp...
(A) Coimmunoprecipitation by anti-IgG, anti-TEAD4, and anti-RAD21 antibodies followed by immunoblotting (IB) with antibodies against the indicated proteins using cell extracts from OVCAR8, OVCAR5, and HEY cells. (B) Colocalization of RAD21 with CTCF (left, positive control), YAP (middle), and TEAD4 (right) was visualized by immunofluorescence. Scale bar: 20 μm. (C) Heatmap for DEGs (P < 0.01, |log2foldchange| > 1) in TEAD4-KD and control OVCAR8 cells (duplicates). (D) Genomic distribution of TEAD4 peaks in OVCAR8 cells. (E) Venn diagram showing the overlaps of DEGs and TEAD4 direct targets obtained from TEAD4 ChIP-Seq results. (F) GSEA analysis showing that the IFN Signaling and IFN-α/β Signaling pathways were enriched in TEAD4-KD cells compared with control cells. (G) Venn diagram (left) and scatterplot (right) showing the precise targets repressed by RAD21 and TEAD4. (H) Genome browser tracks of RAD21 and TEAD4 ChIP-Seq and RNA-Seq at genomic loci of ISG15, IFIT3, IFI44, and DDX58. (I) qRT-PCR validation of representative ISGs in TAED4-KD and control OVCAR8 cells. (J) ChIP-qPCR analysis of RAD21 and TEAD4 occupancy at genomic loci of ISGs ISG15, IFIT3, IFI44, and DDX58 in OVCAR8 cells. Data are shown as mean ± SD (n = 3, 1-way ANOVA). (K) ChIP-qPCR analysis of TEAD4 occupancy at genomic loci of ISGs ISG15, IFIT3, IFI44, and DDX58 in RAD21-KD and control OVCAR8 cells mediated by shRNA. (L) Re-ChIP analysis showing the concurrent presence of both RAD21 and TEAD4 at genomic loci of ISGs ISG15, IFIT3, IFI44, and DDX58. Data in I, K, and L are shown as mean ± SD (n = 3, 2-tailed t test). *P < 0.05; **P < 0.01; ***P < 0.001.