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 1

RAD21 is a critical CNA gene and amplified RAD21 correlates with poor prognosis in HGSOC.

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RAD21 is a critical CNA gene and amplified RAD21 correlates with poor pr...
(A) Bar graph showing the CNA frequencies (191 copy gains and 15 copy loss) in the TCGA-OV database. (B) Venn diagram showing the overlap of 206 CNAs and DEGs in human OV in the TCGA database (TCGA-OV transcriptome_U133A-seq database, adjusted P value < 0.01, |log2foldchange| > 1). (C) Heatmap for upregulated genes (adjusted P value < 0.01) in 10 pairs of independent patients from GSE69428 database. (D) Representative images of colony formation assay in OVCAR8 cells transfected with scramble siRNA or 2 individual siRNAs targeting RAD21, GMPS, CKS1B, and RAD54L, respectively. (E) Integrative Genomics Viewer heatmap displays the CNAs on the RAD21 locus, obtained from data of OV in cBioportal (n = 572; copy number amplification was defined as copy number score > 0.3). (F) Genetic alteration frequency of RAD21 in TCGA pan-cancer database. (G) Correlation analysis showing an increase in RAD21 mRNA level concordant with the gain of an additional DNA copy (Gain) and/or multiple copies (Amp) (Spearman ρ = 0.76; P = 2.36 × 10–57). (H and I) Representative images (H) and quantification (I) of FISH showing RAD21 locus in ovarian tumor (n = 107) and normal fallopian tube tissue (n = 20) from SYSUCC cohort. Blue, DNA stained with DAPI; green, centromere of chromosome 8; red, genomic locus of RAD21 gene. Scale bars: 5 μm. (J and K) Kaplan-Meier curves of recurrence time (J) and overall survival rates (K) in patients with OV grouped according to high (red, n = 67) and low (blue, n = 40) copies of RAD21 (log-rank test). (L and M) Representative IHC staining (L) and quantification (M) showing RAD21 expression in ovarian tumor (n = 107) and normal fallopian tube tissue (n = 20) from SYSUCC cohort. (N and O) Kaplan-Meier curves of recurrence time (N) and overall survival rates (O) in patients with OV grouped according to high (red, n = 53) and low (blue, n = 54) expression of RAD21 (log-rank test). Data in I and M are shown as mean ± SD (2-tailed t test).