R-loop-associated regulator VDAC1 drives malignant phenotypes in uveal melanoma.

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• R-loops are critical for genome stability and transcription.
• Their specific roles in uveal melanoma (UVM) remain largely unknown.

Purpose of the Study:

• To investigate the role of R-loop regulators in UVM.
• To identify key regulators associated with poor prognosis and metastasis in UVM.
• To functionally validate VDAC1 as a potential therapeutic target.

Main Methods:

• Analysis of 1,185 R-loop regulators across TCGA-UVM and GEO datasets.
• ssGSEA for global R-loop activity assessment.
• Integrative bioinformatics screening, shRNA-mediated VDAC1 knockdown, immunofluorescence assays, and in vivo mouse models.

Main Results:

• Elevated R-loop activity scores correlate with advanced UVM stages and metastasis.
• A signature of R-loop regulators, including VDAC1, is linked to high-risk UVM.
• VDAC1 knockdown inhibits proliferation, migration, and induces apoptosis, while increasing R-loop accumulation and DNA damage.

Conclusions:

• VDAC1 is a critical R-loop regulator in UVM, driving genomic instability and tumor progression.
• Dysregulated VDAC1 contributes to the aggressive phenotype of UVM.
• Targeting VDAC1-mediated R-loop homeostasis presents a potential therapeutic strategy for high-risk UVM.