NONO inhibits lymphatic metastasis of bladder cancer via alternative splicing of SETMAR
NONO inhibits lymphatic metastasis of bladder cancer via alternative splicing of SETMAR
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NONO 通过 SETMAR 的选择性剪接抑制膀胱癌的淋巴转移。
DOI：
10.1016/j.ymthe.2020.08.018
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发表时间：
2020
影响因子：
12.4
通讯作者：
Tianxin Lin
中科院分区：
文献类型：
--
作者：
Ruihui Xie;Xu Chen;Liang Cheng;Ming Huang;Qianghua Zhou;Jingtong Zhang;Yuelong Chen;Shengmeng Peng;Ziyue Chen;Wen Dong;Jian Huang;Tianxin Lin
膀胱癌淋巴结转移患者预后极差，且无有效治疗。前体mRNA的选择性剪接参与各种肿瘤的进展。然而，剪接因子和肿瘤相关变异体在膀胱癌LN转移中的确切机制仍不清楚。本研究确定了一种剪接因子，非POU结构域的八聚体结合蛋白（NONO），在膀胱癌组织中显著下调，并与LN转移状态，肿瘤分期和预后相关。在功能上，NONO能显著抑制膀胱癌细胞的体外迁移和侵袭以及体内LN的转移。NONO主要通过RRM 2结构域与SETMAR基序结合来调控SETMAR的外显子跳跃。NONO与剪接因子脯氨酸/谷氨酰胺富集（SFPQ）相互作用，调节SETMAR的剪接，抑制膀胱癌细胞的转移。SETMAR-L过表达可显著逆转NONO敲低的膀胱癌细胞的体内外转移。进一步的分析显示NONO介导的SETMAR-L可以在转移癌基因的启动子处诱导H3 K27 me 3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转移性膀胱癌的临床标志物和治疗策略提供新的思路。
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 invasionin vitroand LN metastasisin 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, bothin vitroandin 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.