SOAT1, also known as acyl-coenzyme A (CoA):cholesterol acyltransferase 1 (ACAT1), is a key enzyme in lipid metabolism. It mediates cholesterol esterification, converting cholesterol to inert cholesterol esters for storage in lipid droplets. This process is crucial for maintaining cholesterol homeostasis, which is essential for various biological processes such as cell membrane integrity, signal transduction, and lipoprotein metabolism [5,6]. Genetic models, like KO/CKO mouse models, have been instrumental in understanding its functions.

In pancreatic cancer, genetic targeting of Soat1 in organoid and mouse models impairs cell proliferation in vitro and tumor progression in vivo, revealing a mevalonate pathway dependency in p53 mutant PDAC cells with p53 loss of heterozygosity (LOH) [2]. In hepatocellular carcinoma, SOAT1 promotes epithelial-mesenchymal transition (EMT), accelerating tumorigenesis and development in HCC xenograft and NAFLD-HCC models. Inhibiting SOAT1 with nootkatone suppresses EMT [1]. In lung cancer, downregulation of SOAT1 in cells inhibits invasion, mitochondrial fragmentation, AKT phosphorylation, and promotes intracellular free cholesterol accumulation [3]. In colorectal cancer, silencing SOAT1 in tumor cells strongly inhibits their migration and invasion ability [4]. In oral squamous cell carcinoma, SOAT1 enhances the malignant phenotype of cancer cells and induces M2-like polarization of tumor-associated macrophages (TAMs) [7].

In conclusion, SOAT1 plays a vital role in maintaining cholesterol homeostasis. Through model-based research, especially KO/CKO mouse models, it has been shown to be involved in the progression of multiple cancers, including pancreatic, liver, lung, colorectal, and oral squamous cell carcinomas. These findings highlight the potential of SOAT1 as a therapeutic target in cancer treatment.

References:

1. Fu, Rongrong, Xue, Wenqing, Liang, Jingjie, Zhang, Min, Meng, Jing. 2024. SOAT1 regulates cholesterol metabolism to induce EMT in hepatocellular carcinoma. In Cell death & disease, 15, 325. doi:10.1038/s41419-024-06711-9. https://pubmed.ncbi.nlm.nih.gov/38724499/

2. Oni, Tobiloba E, Biffi, Giulia, Baker, Lindsey A, Vakoc, Christopher R, Tuveson, David A. . SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. In The Journal of experimental medicine, 217, . doi:10.1084/jem.20192389. https://pubmed.ncbi.nlm.nih.gov/32633781/

3. Mo, Yijun, Lin, Lina, Zhang, Jianhua, Yu, Changhui. 2021. SOAT1 enhances lung cancer invasiveness by stimulating AKT-mediated mitochondrial fragmentation. In Biochemistry and cell biology = Biochimie et biologie cellulaire, 100, 68-74. doi:10.1139/bcb-2021-0175. https://pubmed.ncbi.nlm.nih.gov/34670102/

4. Wang, Xin-Chun, Luo, Lin-Ming, Huang, Tao-Sheng, Feng, Li-Feng. 2021. SOAT1 is a new prognostic factor of colorectal cancer. In Irish journal of medical science, 191, 1549-1554. doi:10.1007/s11845-021-02746-5. https://pubmed.ncbi.nlm.nih.gov/34460058/

5. Liu, Qing, Wu, Xiaolin, Duan, Wei, Zhou, Zhangsen, Zhu, Yuyan. 2024. ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis. In Journal of lipid research, 65, 100680. doi:10.1016/j.jlr.2024.100680. https://pubmed.ncbi.nlm.nih.gov/39481851/

6. Kiener, Sarah, McMahill, Barbara G, Affolter, Verena K, Jagannathan, Vidhya, Leeb, Tosso. 2023. SOAT1 missense variant in two cats with sebaceous gland dysplasia. In Molecular genetics and genomics : MGG, 298, 837-843. doi:10.1007/s00438-023-02020-6. https://pubmed.ncbi.nlm.nih.gov/37060467/

7. Liu, Yueying, Shen, Li, Li, Yi, Jiang, Yiqun, Cong, Li. 2024. ETS1-mediated Regulation of SOAT1 Enhances the Malignant Phenotype of Oral Squamous Cell Carcinoma and Induces Tumor-associated Macrophages M2-like Polarization. In International journal of biological sciences, 20, 3372-3392. doi:10.7150/ijbs.93815. https://pubmed.ncbi.nlm.nih.gov/38993570/