J Cancer 2018; 9(20):3787-3796. doi:10.7150/jca.26275 This issue

Research Paper

EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis

Chenmin Sun1,2, Chunchun Zhao5, Shugen Li5, Jianqing Wang5, Qidong Zhou3, Jianliang Sun3, Qiang Ding3, Min Liu1,4✉, Guanxiong Ding3 ✉

1. Department of Urology, Tongren Hospital, Shanghai JiaoTong University School of Medicine.
2. Department of Anaesthesiology, Tongren Hospital, Shanghai JiaoTong University School of Medicine.
3. Department of Urology, Huashan Hospital, Fudan University.
4. Department of Urology, Shanghai Tenth People's Hospital, Tongji University.
5. Department of Urology, Nanjing Medical University Affiliated Suzhou Hospital.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Sun C, Zhao C, Li S, Wang J, Zhou Q, Sun J, Ding Q, Liu M, Ding G. EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis. J Cancer 2018; 9(20):3787-3796. doi:10.7150/jca.26275. Available from https://www.jcancer.org/v09p3787.htm

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Aim: BAP1 is frequently mutated in clear cell renal cell carcinoma (ccRCC) with a definitive role still unclear.

Methods: In silico analysis of BAP1-mutant and wild-type gene enrichment and functional annotation in TCGA-KIRC dataset was performed. Target gene was studied based on functional clustering and was knowledge-based. Validation using in-house pathological sections were performed immunohistochemically. In vitro and in vivo studies on target gene were performed.

Results: The TCGA ccRCC dataset included 534 ccRCC samples. BAP1 was frequently mutated and more frequently downregulated in ccRCC compared to normal kidney tissue or benign renal tumors. In the analysis between samples with BAP1 mutation (N = 33) and pan-negative (N = 33), we found that cancers with BAP1 mutation was significantly enriched for 14 pathways, of which 3 were DNA repair pathways, in which EZH2 played a role. CcRCC patients with lower BAP1 expression had poor prognosis and showed higher EZH2 expression, which also conferred worsened survival. Genetic and pharmaceutical inhibition of EZH2 not only inhibited BAP1-mutatn ccRCC cell viability and invasion but also abrogated genetic replenishing of BAP1 expression. Validation cohort encompassing 62 ccRCC samples confirmed the worsened phenotype for cases with higher EZH2 expression and significant positive correlation between expressions of EZH2 and BAP1. EZH2 inhibitor also inhibited tumor growth in xenograft mouse model with BAP1-mutated ccRCC cells with unremarkable toxicity.

Conclusion: CcRCC with decreased BAP1 level has poor prognosis and is associated with higher EZH2 expression. Inhibition of EZH2 in BAP1-mutated entity holds promise for further investigation.

Keywords: EZH2 Expression, BAP1-mutant