RAD21 amplification epigenetically suppresses interferon signaling to promote immune evasion in ovarian cancer
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
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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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 2

Genome-wide identification of potential targets of RAD21 and its associated cohesin complexes.

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Genome-wide identification of potential targets of RAD21 and its associa...
(A) Scatterplot of DEGs between RAD21-knockdown (RAD21-KD) and control OVCAR8 cells (duplicates, P < 0.05, |log2foldchange| > 1). (B) Genomic distribution of RAD21 peaks in OVCAR8 cells. (C) Venn diagram showing the overlaps of DEGs and RAD21 direct targets obtained from ChIP-Seq results. (D) The 764 DEGs described in C were functionally clustered using the RECTOME gene sets. The top 5 upregulated and downregulated pathways are shown. (E) GSEA analysis showing that Cytokine Signaling in Immune System and IFN Signaling were enriched among the upregulated pathways. NES, normalized enrichment score. (F) Heatmap for significantly upregulated IFN signaling genes (P < 0.05) in RAD21-KD versus control OVCAR8 cells. (G) qRT-PCR validation of representative ISGs in RAD21-KD and control OVCAR8 cells. Data are shown as mean ± SD (n = 3, 1-way ANOVA). (H) Venn diagram showing the overlaps of RAD21 direct targets and H3K27ac targets. Two clusters (cluster I [common] and cluster II [RAD21 unique]) were divided according to H3K27ac signals. (I) Heatmap showing the binding patterns for RAD21 and H3K27ac at accessible regions of cluster I and cluster II genes. (J) ChIP-qPCR validation of representative ISGs in RAD21-KD and control OVCAR8 cells using antibodies against H3K27ac (left) and RAD21 (right). Data are shown as mean ± SD (n = 3, 2-tailed t test). (K) DNA motif analysis in RAD21 ChIP-Seq peaks showing the significant enrichment of BORIS and TEAD4 motif (hypergeometric test). *P < 0.05; **P < 0.01; ***P < 0.001.