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Methylation-mediated silencing of Dlg5 facilitates bladder cancer metastasis
Zhihua Zhou1, Yifeng Guo1, Yong Liu1
1Department of Urology, Shanghai First People׳s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200008, China.
Unlabelled:
Dlg5 (Discs large homolog 5), a member of the membrane-associated guanylate kinase adaptor family of scaffolding proteins, has been shown to participate in cancer progression. However, little is known about whether abnormal expression of Dlg5 facilitates bladder cancer metastasis. In the current study we initiated a study analyzing Dlg5 expression and its roles in human bladder cancer metastasis. The expression of Dlg5 is decreased in most bladder cancer tissues compared with adjacent normal tissues, and Dlg5 expression is further downregulated in patients with muscle-invasive tumors. DNA methylation analysis showed a methylation of Dlg5 gene in bladder cancer cell lines and in bladder cancer tumors, especially in muscle-invasive tumors. Hypermethylation of Dlg5 in bladder tumors is tightly correlated with silencing of Dlg5 expression, which is further functionally validated by demethylation analysis in bladder cancer cell lines. Knockdown of Dlg5 increases cancer cell invasion in vitro and promotes cancer metastasis in vivo. Of clinical significance, Kaplan-Meier analysis showed that downregulation of Dlg5 is significantly associated with reduced overall survival in patients with bladder cancer.
Conclusion:
These data suggest that inhibition of Dlg5 by DNA hypermethylation contributes to provoke invasive phenotypes in bladder tumor.
Insights
Discs large homolog 5 (Dlg5) downregulation, driven by DNA hypermethylation, promotes bladder cancer metastasis and predicts poor survival. Loss of Dlg5 function enhances tumor invasiveness.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Discs large homolog 5 (Dlg5) is a scaffolding protein implicated in cancer progression.
- The specific role of Dlg5 in bladder cancer metastasis remains largely unexplored.
Purpose of the Study:
- To investigate the expression patterns of Dlg5 in human bladder cancer.
- To elucidate the functional significance of Dlg5 in bladder cancer metastasis and its association with patient survival.
Main Methods:
- Analysis of Dlg5 expression in bladder cancer tissues and adjacent normal tissues.
- DNA methylation analysis of the Dlg5 gene in bladder cancer cell lines and tumors.
- Functional studies involving Dlg5 knockdown to assess effects on cell invasion and metastasis.
- Kaplan-Meier survival analysis to correlate Dlg5 expression with patient outcomes.
Main Results:
- Dlg5 expression is significantly decreased in bladder cancer tissues, particularly in muscle-invasive tumors.
- DNA hypermethylation of the Dlg5 gene correlates with its reduced expression in bladder tumors.
- Knockdown of Dlg5 enhances bladder cancer cell invasion in vitro and promotes metastasis in vivo.
- Downregulation of Dlg5 is significantly associated with reduced overall survival in bladder cancer patients.
Conclusions:
- DNA hypermethylation-induced inhibition of Dlg5 contributes to the invasive phenotype of bladder tumors.
- Dlg5 acts as a tumor suppressor in bladder cancer, and its downregulation is a marker for poor prognosis.
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