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Long non-coding RNA DBCCR1-003 regulate the expression of DBCCR1 via DNMT1 in bladder cancer
Defeng Qi1, Jinhui Li1,2, Biao Que1
1Guangdong Key Laboratory of Urology, Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Kangda Road 1#, Haizhu District, Guangzhou, 510230 Guangdong China.
Background:
Many long non coding RNAs have been identified as key modulators in cancer development. A lncRNA, DBCCR1-003, derived from the locus of tumor suppressor gene DBCCR1 (deleted in bladder cancer chromosome region 1), has unknown function. In the present study, we explored function and molecular mechanism of DBCCR1-003 in bladder cancer (BC) development.
Methods:
We evaluated the expression levels of DBCCR1-003 in tissues and cells with western blot and quantitative real-time polymerase chain reaction. Multiple approaches including chromatin immunoprecipitation assay and RNA immunoprecipitation were used to confirm the direct binding of DBCCR1-003 to DNMT1. The recombinant vector overexpressing DBCCR1-003 was constructed. Cell proliferation assay, colony formation assay and flow cytometric analysis were employed to measure the role of DBCCR1-003 in regulation of cell proliferation, cycle and apoptosis.
Results:
Firstly we detected the expression of DBCCR1-003, DBCCR1, DNMT1 (DNA methyltransferase 1) and DNA methylation in the promoter of DBCCR1. We found low expression of DBCCR1-003, same as DBCCR1, while high expression of DNMT1 and hypermethylation of DBCCR1 gene promoter in BC tissues and T24 cells line. Further studies revealed that treatment of DNMT inhibitor, 5-aza-2-deoxycytidine(DAC), or overexpression of DBCCR1-003 led to increased DBCCR1 expression by reversion of promoter hypermethylation and DNMT1 binding to DBCCR1 promoter in T24 cells. Importantly, RNA immunoprecipitation (RIP) showed that DBCCR1-003 physically associates with DNMT1. The binding of them was increased with the inhibition of DBCCR1 promoter methylation, indicating that DBCCR1-003 may bind to DNMT1 and prevent DNMT1-mediated the methylation of DBCCR1. Furthermore, overexpression of DBCCR1-003 resulted in significant inhibition of T24 cells growth through the inducing G0/G1 arrest and apoptosis.
Conclusions:
Taken together, these findings demonstrated that a novel tumor suppressor DBCCR1-003 regulates the expression of DBCCR1 via binding to DNMT1 and preventing DNMT1-mediated the methylation of DBCCR1 in BC. LncRNA DBCCR1-003 may serve as a novel biomarker and therapeutic target for BC in future cancer clinic.
Insights
A novel long non-coding RNA, DBCCR1-003, acts as a tumor suppressor in bladder cancer (BC). It inhibits DNA methyltransferase 1 (DNMT1) activity, preventing DBCCR1 gene methylation and promoting cell cycle arrest and apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Long non-coding RNAs (lncRNAs) are crucial in cancer development.
- The function of DBCCR1-003, a lncRNA from the DBCCR1 tumor suppressor locus, in bladder cancer (BC) was previously unknown.
Purpose of the Study:
- To investigate the function and molecular mechanism of DBCCR1-003 in bladder cancer (BC).
- To explore DBCCR1-003's role in regulating gene expression and cell behavior within BC.
Main Methods:
- Quantitative real-time PCR and western blot to assess expression levels of DBCCR1-003, DBCCR1, and DNMT1.
- Chromatin immunoprecipitation and RNA immunoprecipitation assays to confirm direct binding of DBCCR1-003 to DNMT1.
- Cell proliferation, colony formation, and flow cytometry assays to evaluate the impact of DBCCR1-003 on cell growth, cycle, and apoptosis.
Main Results:
- BC tissues and T24 cells exhibited low DBCCR1-003 and DBCCR1 expression, alongside high DNMT1 expression and DBCCR1 promoter hypermethylation.
- Overexpression of DBCCR1-003 or treatment with a DNMT inhibitor (5-aza-2-deoxycytidine) reversed DBCCR1 promoter hypermethylation and increased DBCCR1 expression.
- DBCCR1-003 physically associates with DNMT1, inhibiting DNMT1-mediated methylation of the DBCCR1 promoter.
Conclusions:
- DBCCR1-003 functions as a tumor suppressor in BC by binding to DNMT1 and preventing DBCCR1 methylation.
- LncRNA DBCCR1-003 shows potential as a biomarker and therapeutic target for bladder cancer.
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