IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming

Abstract

Ovarian cancer (OC) is often detected at an advanced stage and has a high recurrence rate after surgery or chemotherapy. Thus, it is essential to develop new strategies for OC treatment. This study tended to investigate the effects of endothelial cell-specific molecule 1 (ESM1) in OC. The impact of ESM1 on lipid metabolism was investigated through the regulation of ESM1 expression. Differential genes regulated by ESM1 were screened by mRNA sequencing. The role of autophagy in ESM1 regulation on lipid metabolism was explored using autophagy inhibitor chloroquine (CQ). Co-IP, dual-luciferase reporter assay, actinomycin D treatment assay, and others were used to analyze the mechanism of ESM1 regulation on lipid metabolism. The xenograft mouse model was constructed to explore the impact of ESM1 regulation on OC development. The regulatory mechanism of ESM1 in OC patient samples was verified by using microarray analysis and the Log-rank (Mantel-Cox) test. After ESM1 silencing, cholesterol synthesis decreased and lipolysis increased. mRNA sequencing revealed that ESM1 regulation on lipid metabolism was related to Beclin 1 (BECN1). In vitro experiments, ESM1 inhibited lipolysis by suppressing BECN1-mediated autophagy. BECN1 expression was regulated by the transcription factor Kruppel-like factor 10 (KLF10). The competitive binding between BECN1 and HSPA5 promoted the ubiquitination degradation of HMGCR, thereby inhibiting cholesterol production. The intervention experiment with exogenous cholesterol showed a positive correlation between m6A reader IGF2BP3 expression and cholesterol content. Mechanistically, IGF2BP3 regulated the stability of ESM1 mRNA. In vivo experiments, ESM1 modified by m6A methylation promoted cholesterol synthesis and inhibited lipolysis. High expression of ESM1 predicted poor prognosis in OC patients. ESM1 regulated lipid metabolism through IGF2BP3/ESM1/KLF10/BECN1 positive feedback, which was a promising target for OC treatment.