VAV2 exists in extrachromosomal circular DNA and contributes Enzalutamide resistance of prostate cancer via stabilization of AR/ARv7.

Extrachromosomal circular DNAs (eccDNAs) are circular, double-stranded DNA molecules ubiquitously present across various organisms, playing a critical role in tumorigenesis and tumor progression. However, their precise contribution to prostate cancer (PCa) remains incompletely understood. To elucidate the function of eccDNAs in PCa, eccDNA sequencing and annotation were performed in PCa tissues and cell lines using Circle-seq. Amplified genes on eccDNAs were identified by cross-referencing annotated eccDNA-associated genes with those overexpressed in PCa based on TCGA data. Furthermore, eccDNA profiles were compared between Enzalutamide-sensitive and -resistant cell lines to investigate their role in resistance mechanisms. Notably, VAV2 was detected on both linear and circular DNA, as confirmed by PCR and Sanger sequencing. Functional analyses demonstrated that VAV2 overexpression promotes PCa proliferation and metastasis by activating the PAK1/AKT signaling pathway through PAK1 phosphorylation. Additionally, VAV2 contributes to Enzalutamide resistance by enhancing AR/ARv7 protein stability via reduced ubiquitination, mediated through the recruitment of the deubiquitinating enzyme USP48. These findings establish VAV2, identified through eccDNA sequencing, as a potential oncogene and a promising biomarker for PCa diagnosis and prognosis.