Abstract
BACKGROUND: Although androgen receptor (AR)-targeted therapies have shown notable clinical efficacy in prostate cancer (PCa), the emergence of drug resistance remains a critical factor driving the clinical prognosis in castration-resistant prostate cancer (CRPC). Aberrant tumor lipid metabolism not only fulfills the energetic and biosynthetic requirements of rapidly proliferating cancer cells but also contributes to the development of therapeutic resistance. METHODS: We examined SOX8 expression in enzalutamide resistance (EnzR) cell lines and validated its association with tumor progression and clinical outcome. The malignant phenotypes related to EnzR were assessed in vitro using PCa cell lines with stable SOX8 overexpression or knockdown. Tumor xenografts were subsequently generated by inoculating the corresponding cell lines into nude mice. To elucidate the underlying mechanisms, we conducted RNA-seq, CUT&Tag, non-targeted metabolomics, and a series of molecular and biochemical assays. RESULTS: SOX8 expression was elevated in EnzR prostate cancer cell lines and positively correlated with poor patient prognosis. Reduced SOX8 expression enhanced cellular sensitivity to enzalutamide, whereas elevated SOX8 expression decreased drug responsiveness. Chromatin immunoprecipitations (ChIP) assays revealed that AR was enriched at the SOX8 promoter region and transcriptionally repressed SOX8. In vivo, stable SOX8 knockdown markedly suppressed tumor growth in nude mouse xenografts. Mechanistically, SOX8 promotes the EnzR by reprograming lipid metabolism and we identified carnitine palmitoyltransferase 2 (CPT2), a key enzyme in lipid metabolism, as a novel downstream target of SOX8. SOX8-driven lipid metabolic reprogramming promoted enzalutamide resistance through the SOX8/CPT2 axis. CONCLUSIONS: High SOX8 expression promotes EnzR in PCa, suggesting SOX8 as a potential therapeutic target. Our findings demonstrate that SOX8 drives EnzR by activating the SOX8/CPT2 axis, thereby inducing lipid metabolic reprogramming in PCa cells.