Vitamin D promotes DNase1L3 to degrade ecDNA and inhibit the malignant progression of hepatocellular carcinoma

Extrachromosomal DNA (ecDNA) is an important carrier of oncogene amplification. However, the degradation mechanism of ecDNA is not well understood. We found that endogenous natural molecular vitamin D (VD) reduces ecDNA and inhibits the progression of hepatocellular carcinoma (HCC). VD reduces ecDNA depending on its transporter GC, which interacts with the endonuclease DNase1L3 and stabilize its protein level. DNase1L3 with its lipophilic region on N-terminus exhibiting an affinity towards lipid droplets (LDs) demonstrates direct degradation effect on ecDNA. Intranuclear LDs are abundantly distributed around ecDNA, DNase1L3 therefore shows an affinity for ecDNA owing to its lipophilic region. VD, as a lipid-soluble molecule, can increase the size of LDs and improve the degradation of DNase1L3 on ecDNA. Consequently, we designed two mRNA-based therapeutics, DNase1L3 and GC-DNase, both of which had an anti-tumor effect on PDX models. The above results showed that treatments targeting ecDNA in cancer are prospective in clinical practice.