Targeting sterol-O-acyltransferase 1 to disrupt cholesterol metabolism for cancer therapy

Abstract

Cholesterol esterification is often dysregulated in cancer. Sterol O-acyl-transferase 1 (SOAT1) plays an important role in maintaining cellular cholesterol homeostasis by catalyzing the formation of cholesterol esters from cholesterol and long-chain fatty acids in cells. Many studies have implicated that SOAT1 plays a vital role in cancer initiation and progression and is an attractive target for novel anticancer therapy. In this review, we provide an overview of the mechanism and regulation of SOAT1 in cancer and summarize the updates of anticancer therapy targeting SOAT1.

Keywords: avasimibe; cancer therapy; cholesterol esterification; cholesterol metabolism; sterol-O-acyltransferase 1.

Figure 1

Cholesterol metabolism centered on SOAT1. Cholesterol acquisition by cells occurs through de novo synthesis in the endoplasmic reticulum (ER) and via LDLR-mediated endocytosis of LDL. SOAT1 is an ER-associated enzyme responsible for cholesterol storage. SOAT1-mediated esterification of increased cholesterol and fatty acids results in the formation of CE, which is stored in lipid droplets. SREBP cleavage-activating protein (SCAP) is a cholesterol sensing protein and forms a complex with SREBP2 and an ER membrane anchor protein insulin-induced gene (INSIG). A decrease in cholesterol levels within the endoplasmic reticulum (ER) results in the dissociation of INSIG from SCAP, thereby releasing the SCAP/SREBP2 complex. Subsequently, SREBP2 is transported to the Golgi complex and undergoes proteolytic activation by the site-1 and site-2 proteases (S1P and S2P). The N-terminal domain of SREBP2 then translocates to the nucleus to initiate gene transcription necessary for cholesterol synthesis and uptake.