NSUN2-Mediated R-loop Stabilization as a Key Driver of Bladder Cancer Progression and Cisplatin Sensitivity

Yuqing Wu; Yufan Ying; Fenghao Zhang; Xuan Shu; Zhixiang Qi; Jiaming Wang; Zixiang Liu; Yijie Tang; Jiazhu Sun; Jiahe Yi; Dingheng Lu; Shen Lin; Sida Hao; Xueyou Ma; Jiangfeng Li; Xiao Wang; Liping Xie; Xiangyi Zheng

doi:10.1016/j.canlet.2024.217416

NSUN2-Mediated R-loop Stabilization as a Key Driver of Bladder Cancer Progression and Cisplatin Sensitivity

Cancer Lett. 2024 Dec 26:217416. doi: 10.1016/j.canlet.2024.217416. Online ahead of print.

Authors

Yuqing Wu¹, Yufan Ying², Fenghao Zhang³, Xuan Shu³, Zhixiang Qi³, Jiaming Wang³, Zixiang Liu⁴, Yijie Tang³, Jiazhu Sun³, Jiahe Yi³, Dingheng Lu³, Shen Lin³, Sida Hao³, Xueyou Ma¹, Jiangfeng Li¹, Xiao Wang⁵, Liping Xie⁶, Xiangyi Zheng⁷

Affiliations

¹ Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
² Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address: [email protected].
³ Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
⁴ Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315042, China.
⁵ Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address: [email protected].
⁶ Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address: [email protected].
⁷ Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address: [email protected].

PMID: 39732321
DOI: 10.1016/j.canlet.2024.217416

Abstract

R-loops are critical structures that play pivotal roles in regulating genomic stability and modulating gene expression. This study investigates the interactions between the 5-methylcytosine (m⁵C) methyltransferase NOP2/Sun RNA methyltransferase 2 (NSUN2) and R-loops in the transcriptional dynamics and damage repair process of bladder cancer (BCa) cells. We observed markedly elevated levels of R-loops in BCa cells relative to normal urothelial cells. NSUN2 was identified as a regulator of R-loops, acting to bind and stabilize their structure through a process dependent on its m⁵C catalytic activity. The histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) was found to interact with NSUN2. Our results demonstrated that NSUN2 facilitates the epigenetic silencing of the tumor suppressor gene PR Domain Zinc Finger Protein 11 (PRDM11) by recruiting EZH2, thereby advancing the progression of BCa. Furthermore, NSUN2 knockdown sensitizes tumors to cisplatin, resulting in reduced tumor growth and increased DNA damage levels, which was associated with reduced recruitment of MRE11 to damage sites, thereby impairing homologous recombination repair. These findings enhance our understanding of BCa pathogenesis and identify new potential targets for therapeutic intervention.

Keywords: Bladder cancer; H3K27me3; Homologous recombination; M(5)C; MRE11; NSUN2; R-loops.