Abstract 5702: Knockdown of COP1 disrupts lipid metabolism and reduces migration ability in hepatocellular carcinoma cells

Abstract Hepatocellular carcinoma (HCC) is one of the cancers with the highest mortality rates worldwide, being the sixth most commonly diagnosed cancer globally and the third leading cause of cancer-related deaths. COP1 gene, an E3-ubiquitin ligase, is generally overexpressed in human HCC and that plays an important role in the degradation of p53 tumor suppressor via ubiquitination. We have previously defined the COP1 gene as a therapeutic target in HCC. A recent study demonstrated that COP1 induces nonalcoholic fatty liver disease (NAFLD) in normal hepatocytes and that reducing COP1 expression in the liver significantly improves high-fat diet-induced hepatic steatosis. Thus in this study, we investigated if the function of COP1 was associated with HCC metabolism as well. siRNA-mediated inhibition of COP1 expression suppressed long-term colony formation in both Huh7 and HepG2 HCC cell lines. RNA sequencing of COP1-silenced HCC cells revealed the same directional regulation of 24 (10 down- and 14 up-regulated) genes. Notably, AKR1D1 gene, which negatively regulates bile acid biosynthesis and lipid metabolism, was up-regulated and that TMEM65 gene, which promotes migration and invasion of cancer cells, was down-regulated. Correlation analysis using publicly available databases further supported an inverse relationship between COP1 and AKR1D1 expression in HCC. Subsequent studies showed that COP1 knockdown inhibits synthesis of cellular lipids through the downregulation of GLUT4, DGAT2, FASN, and ChREBPα genes that are functionally involved in glucose transport or fatty acid synthesis. Furthermore, silencing of COP1 significantly reduced the abilities of migration and sphere formation in HCC parental cell population. Collectively, our findings indicate that the function of COP1 is associated with HCC lipid metabolism and migration. Citation Format: Hun-Mo Ryoo, Eun-Hye Jeon, Keon Uk Park, Ilseon Hwang, Yun-Han Lee. Knockdown of COP1 disrupts lipid metabolism and reduces migration ability in hepatocellular carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5702.