APOL2 Stabilizes Ku80 to Confer NHEJ-Mediated Radioresistance in Gastric Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Radiotherapy is a critical adjuvant treatment for gastric cancer (GC).
• Radioresistance significantly limits the clinical efficacy of radiotherapy in GC.
• Identifying novel targets to overcome radioresistance is crucial for improving GC patient outcomes.

Purpose of the Study:

• To investigate the role of APOL2 in gastric cancer radioresistance.
• To elucidate the molecular mechanisms by which APOL2 influences DNA repair and radiosensitivity.
• To identify potential therapeutic strategies to re-sensitize GC cells to radiotherapy.

Main Methods:

• Bioinformatic analysis of clinical data to correlate APOL2 expression with GC prognosis.
• Functional experiments including gene overexpression and knockout to assess APOL2's impact on DNA repair and radiosensitivity.
• Mechanistic studies involving protein interaction and ubiquitination assays to define APOL2's role in the NHEJ pathway.
• High-throughput screening to identify small molecules targeting the APOL2-Ku80 interaction.

Main Results:

• High APOL2 expression is significantly correlated with poor prognosis in GC patients.
• APOL2 overexpression enhances non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair, promoting genomic stability and radioresistance.
• APOL2 stabilizes Ku80 protein levels via USP7-mediated deubiquitylation, thereby facilitating NHEJ repair.
• Formononetin (FN) was identified as a small molecule inhibitor that disrupts the APOL2-Ku80 interaction, restoring radiosensitivity in GC cells.

Conclusions:

• APOL2 plays a critical role in mediating radioresistance in gastric cancer by stabilizing Ku80 and promoting NHEJ-mediated DNA repair.
• Targeting the APOL2-Ku80 interaction presents a promising therapeutic strategy to overcome radioresistance in GC.
• Formononetin is a potential therapeutic agent for combination therapy to enhance the effectiveness of radiotherapy in gastric cancer treatment.