Defect of MLH1 expression sensitized esophageal squamous cell carcinoma cells to Polθ inhibitor

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• MLH1 (MutL Homolog 1) is a key mismatch repair gene.
• The role of MLH1 in DNA double-strand break (DSB) repair is not fully understood.
• Large-scale studies on MLH1 methylation in esophageal cancer are limited.

Purpose of the Study:

• To investigate the prevalence and prognostic significance of MLH1 methylation in esophageal cancer.
• To elucidate the role of MLH1 in DNA repair pathways.
• To explore potential therapeutic vulnerabilities associated with MLH1 deficiency.

Main Methods:

• Analysis of MLH1 methylation in 1018 esophageal cancer samples using methylation-specific PCR.
• Western blot analysis and CRISPR/Cas9 gene editing to study MLH1 function.
• Correlation analysis with clinical parameters and survival data.

Main Results:

• MLH1 methylation was found in 3.93% of esophageal cancer cases.
• MLH1 methylation correlated significantly with poor tumor differentiation, male gender, smoking, and larger tumor size.
• Patients with MLH1 methylation had significantly shorter overall survival (OS).
• MLH1 methylation was identified as an independent poor prognostic marker.
• MLH1 influences DNA repair pathways, including NHEJ and MMEJ, and its deletion sensitizes cells to novobiocin, a Polθ inhibitor.

Conclusions:

• MLH1 methylation is a significant negative prognostic factor in esophageal cancer.
• MLH1 is involved in regulating DNA double-strand break repair pathways.
• Targeting Polθ with inhibitors like novobiocin may be effective in MLH1-deficient esophageal cancers.