Extrachromosomal circular DNA-related SPOCK1 contributes to development and enzalutamide resistance of prostate cancer by regulating epithelial mesenchymal transition.

Prostate cancer is a significant contributor to cancer-related mortality, and the tumor typically develops into castration-resistant prostate cancer (CRPC). Hence, few effective clinical strategies are available to patients with advanced disease. Extrachromosomal circular DNA (eccDNA) is a type of circular DNA originating from the chromosomes but is likely independent of them. Because of its unique structural characteristics, eccDNA has extensive applications as a new biomarker for cancer prevention and treatment. Circle-seq obtains a comprehensive picture of the overall landscape of eccDNA sizes and content in cell populations. In this study, we used Circle-seq and studied the distribution pattern and expression level of eccDNA in prostate cancer. We confirmed that eccDNA is derived from every human chromosome and has sequences from all known types of genomic structures, revealing it is a common mutational element in prostate cancer. We also identified an eccDNA-related gene SPOCK1 that promotes drug resistance, proliferation, and metastasis of many cancers through the epithelial-mesenchymal transition (EMT) mechanism. The SPOCK1-associated eccDNA was highly upregulated in various groups of sequencing results, and SPOCK1 was highly expressed in prostate cancer tissues and cells. Therefore, SPOCK1 exists as eccDNA in prostate cancer and encourages its development and drug resistance via the EMT mechanism. Our results suggest that upregulated genes in the form of eccDNA are oncogenes in prostate cancer and play a pivotal role in carcinogenesis.