UHRF1-mediated tumor suppressor gene inactivation in nonsmall cell lung cancer
Alexandros Daskalos1, Urszula Oleksiewicz, Anastasia Filia
1Roy Castle Lung Cancer Research Programme, University of Liverpool, Department of Clinical and Molecular Cancer Medicine, Liverpool, United Kingdom.
Background:
The UHRF1 gene possesses an essential role in DNA methylation maintenance, but its contribution to tumor suppressor gene hypermethylation in primary human cancers currently remains unclear.
Methods:
mRNA expression levels of UHRF1, DNMT1, DNMT3A, DNMT3B, and E2F1 were evaluated in 105 primary nonsmall cell lung carcinomas by quantitative polymerase chain reaction. The methylation status of CDKN2A and RASSF1 promoters was examined by pyrosequencing. UHRF1 was knocked down by short hairpin RNA in A549 lung adenocarcinoma cells.
Results:
All 4 genes were overexpressed in a coordinated manner in the lung tumor tissues, and their expression correlated with that of E2F1. Higher UHRF1 expression in tumor tissues correlated with the hypermethylation of CDKN2A (P = .005) and RASSF1 promoters (P = .034), and the relationship with a combined epigenotype was even stronger (P = 2.3 × 10(-4) ). When UHRF1 was knocked down in A549 lung adenocarcinoma cells, lower methylation levels of RASSF1, CYGB, and CDH13 promoters were observed. Also, UHRF1 knockdown clones demonstrated reduced proliferation and decreased cell migration properties.
Conclusions:
Our data demonstrate that UHRF1 is a key epigenetic switch, which controls cell cycle in nonsmall cell lung carcinoma through its ability to sustain the transcriptional silencing of tumor suppressor genes by maintaining their promoters in a hypermethylated status. Thus, UHRF1 should be considered, along with DNMTs, among the potential targets for cancer treatment and/or therapeutic stratification.
Insights
UHRF1 gene overexpression drives tumor suppressor gene hypermethylation and cell cycle control in nonsmall cell lung carcinoma. This epigenetic regulator is a potential therapeutic target for lung cancer treatment.
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Research
Background:
- The UHRF1 gene is crucial for DNA methylation maintenance.
- Its role in tumor suppressor gene hypermethylation in primary human cancers is not fully understood.
Purpose of the Study:
- To investigate the role of UHRF1 in DNA methylation and cell cycle regulation in nonsmall cell lung carcinoma (NSCLC).
- To explore UHRF1 as a potential therapeutic target in NSCLC.
Main Methods:
- Quantitative PCR to measure mRNA expression of UHRF1, DNMTs, and E2F1 in 105 primary NSCLC tissues.
- Pyrosequencing to assess methylation status of CDKN2A and RASSF1 promoters.
- Short hairpin RNA (shRNA) to knockdown UHRF1 in A549 lung adenocarcinoma cells.
Main Results:
- UHRF1, DNMTs, and E2F1 were coordinately overexpressed in NSCLC tissues.
- Higher UHRF1 expression correlated with hypermethylation of CDKN2A and RASSF1 promoters.
- UHRF1 knockdown reduced methylation of tumor suppressor gene promoters and impaired cell proliferation and migration.
Conclusions:
- UHRF1 acts as an epigenetic switch controlling cell cycle in NSCLC by maintaining tumor suppressor gene promoters in a hypermethylated state.
- UHRF1, alongside DNA methyltransferases (DNMTs), represents a promising target for NSCLC therapy and stratification.
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