Details

Autor(en) / Beteiligte

• Xie, Ruihui
• Chen, Xu
• Cheng, Liang
• Huang, Ming
• Zhou, Qianghua
• Zhang, Jingtong
• Chen, Yuelong
• Peng, Shengmeng
• Chen, Ziyue
• Dong, Wen
• Huang, Jian
• Lin, Tianxin

Titel

NONO Inhibits Lymphatic Metastasis of Bladder Cancer via Alternative Splicing of SETMAR

Ist Teil von

• Molecular therapy, 2021-01, Vol.29 (1), p.291-307

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] Xie et al. identify that NONO is a lymphatic metastasis-related splicing factor and a prognostic marker in bladder cancer. NONO inhibits invasion in vitro and lymph node metastasis in vivo via regulating splicing of SETMAR. These findings may provide novel clinical markers and therapeutic strategies for bladder cancer.