Xie Ruihui, Chen Xu, Cheng Liang, Huang Ming, Zhou Qianghua, Zhang Jingtong, Chen Yuelong, Peng Shengmeng, Chen Ziyue, Dong Wen, Huang Jian, Lin Tianxin
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Mol Ther. 2021 Jan 6;29(1):291-307. doi: 10.1016/j.ymthe.2020.08.018. Epub 2020 Sep 5.
Bladder cancer patients with lymph node (LN) metastasis have an extremely poor prognosis and no effective treatment. The alternative splicing of precursor (pre-)mRNA participates in the progression of various tumors. However, the precise mechanisms of splicing factors and cancer-related variants in LN metastasis of bladder cancer remain largely unknown. The present study identified a splicing factor, non-POU domain-containing octamer-binding protein (NONO), that was significantly downregulated in bladder cancer tissues and correlated with LN metastasis status, tumor stage, and prognosis. Functionally, NONO markedly inhibited bladder cancer cell migration and invasion in vitro and LN metastasis in vivo. Mechanistically, NONO regulated the exon skipping of SETMAR by binding to its motif, mainly through the RRM2 domain. NONO directly interacted with splicing factor proline/glutamine rich (SFPQ) to regulate the splicing of SETMAR, and it induced metastasis suppression of bladder cancer cells. SETMAR-L overexpression significantly reversed the metastasis of NONO-knockdown bladder cancer cells, both in vitro and in vivo. The further analysis revealed that NONO-mediated SETMAR-L can induce H3K27me3 at the promotor of metastatic oncogenes and inhibit their transcription, ultimately resulting in metastasis suppression. Therefore, the present findings uncover the molecular mechanism of lymphatic metastasis in bladder cancer, which may provide novel clinical markers and therapeutic strategies for LN-metastatic bladder cancer.
伴有淋巴结（LN）转移的膀胱癌患者预后极差且无有效治疗方法。前体（pre-）mRNA的可变剪接参与多种肿瘤的进展。然而，剪接因子和癌症相关变体在膀胱癌LN转移中的精确机制仍 largely未知。本研究鉴定出一种剪接因子，即含非POU结构域的八聚体结合蛋白（NONO），其在膀胱癌组织中显著下调，并与LN转移状态、肿瘤分期及预后相关。在功能上，NONO在体外显著抑制膀胱癌细胞迁移和侵袭，在体内抑制LN转移。机制上，NONO通过与其基序结合调控SETMAR的外显子跳跃，主要通过RRM2结构域。NONO直接与富含脯氨酸/谷氨酰胺的剪接因子（SFPQ）相互作用以调控SETMAR的剪接，并诱导膀胱癌细胞转移抑制。SETMAR-L过表达在体外和体内均显著逆转NONO敲低的膀胱癌细胞的转移。进一步分析显示，NONO介导的SETMAR-L可在转移癌基因启动子处诱导H3K27me3并抑制其转录，最终导致转移抑制。因此，本研究结果揭示了膀胱癌淋巴转移的分子机制，这可能为LN转移的膀胱癌提供新的临床标志物和治疗策略。
