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

Abstract

AbstractExtrachromosomal 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. VD reduces ecDNA depending on its binding protein GC, which can interact with the endonuclease DNase1L3 and stabilize DNase1L3 protein level. The DNase1L3 protein directly degrades ecDNA, and its N-terminus has a lipophilic region capable of affinity for lipid droplets. Intranuclear lipid droplets are abundantly distributed around ecDNA, so DNase1L3 can affinitize ecDNA through its lipophilic region. VD, as a lipid-soluble molecule, can increase the area of lipid droplets and further improve the degradation of DNase1L3 on ecDNA. Therefore, 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.One-Sentence SummaryVitamin D reduces ecDNA and inhibits cancer progression. DNase1L3 was found to degrade ecDNA with the help of lipid droplets.