Sqle, squalene epoxidase, is a key rate-limiting enzyme in cholesterol biosynthesis [2,3,4,5,6,7]. It is involved in multiple cellular processes related to cholesterol metabolism. Cholesterol and its metabolites play important roles in cancer, and Sqle-mediated cholesterol metabolism is associated with various signaling pathways, such as Src/PI3K/Akt, PTEN/AKT/GSK3β, and TGFβ/SMAD [1,2,4]. Understanding its function is crucial for revealing the mechanisms of diseases, especially cancer. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, can help explore its in-vivo functions.

In cancer research, Sqle has been found to play oncogenic roles. In pancreatic cancer, its inhibition led to squalene accumulation-induced endoplasmic reticulum (ER) stress and apoptosis, while its overexpression promoted tumor growth by activating the Src/PI3K/Akt signaling pathway [1]. In bladder cancer, Sqle knockdown inhibited tumor cell proliferation and metastasis through the PTEN/AKT/GSK3β signaling pathway, and P53 was identified as a key molecule in this regulation [2]. In osteosarcoma, SQLE promoted cell proliferation, migration, and invasion via activating the TGFβ/SMAD signaling pathway, and knockdown of SQLE suppressed these tumor-promoting effects [4]. In high-grade serous ovarian carcinoma (HGSOC), SQLE was upregulated, promoted cancer cell proliferation, and enhanced cancer stem-like cell properties [6]. In NAFLD-induced hepatocellular carcinoma (HCC), hepatocyte-specific Sqle transgenic expression in mice accelerated HCC development, and the SQLE inhibitor terbinafine suppressed tumor growth [7].

In conclusion, Sqle is essential in cholesterol metabolism and significantly impacts cancer development. Studies using KO/CKO mouse models and other loss-of-function experiments in various cancer types, such as pancreatic, bladder, osteosarcoma, HGSOC, and NAFLD-HCC, have revealed its oncogenic roles. These findings suggest that targeting Sqle could be a potential therapeutic strategy for treating related cancers.

References:

1. Xu, Ruiyuan, Song, Jianlu, Ruze, Rexiati, Wang, Chengcheng, Zhao, Yupei. 2023. SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway. In Cell death & disease, 14, 497. doi:10.1038/s41419-023-05987-7. https://pubmed.ncbi.nlm.nih.gov/37542052/

2. Zou, Fan, Chen, Wu, Song, Tianbao, Yu, Weimin, Cheng, Fan. 2023. SQLE Knockdown inhibits bladder cancer progression by regulating the PTEN/AKT/GSK3β signaling pathway through P53. In Cancer cell international, 23, 221. doi:10.1186/s12935-023-02997-5. https://pubmed.ncbi.nlm.nih.gov/37770925/

3. Zhang, Jiapeng, Xu, Hang, He, Yirui, Tan, Ping, Wei, Qiang. 2024. Inhibition of KDM4A restricts SQLE transcription and induces oxidative stress imbalance to suppress bladder cancer. In Redox biology, 77, 103407. doi:10.1016/j.redox.2024.103407. https://pubmed.ncbi.nlm.nih.gov/39461328/

4. Song, Qi, He, Lina, Feng, Jing. 2024. SQLE promotes osteosarcoma progression via activating TGFβ/SMAD signaling pathway. In Molecular and cellular probes, 78, 101993. doi:10.1016/j.mcp.2024.101993. https://pubmed.ncbi.nlm.nih.gov/39608425/

5. Xu, Huanji, Zhou, Sheng, Tang, Qiulin, Xia, Hongwei, Bi, Feng. 2020. Cholesterol metabolism: New functions and therapeutic approaches in cancer. In Biochimica et biophysica acta. Reviews on cancer, 1874, 188394. doi:10.1016/j.bbcan.2020.188394. https://pubmed.ncbi.nlm.nih.gov/32698040/

6. Hou, Rui, Sun, Xinrui, Cao, Shiyao, Wang, Yadong, Jiang, Luo. 2024. Stabilization of SQLE mRNA by WTAP/FTO/IGF2BP3-dependent manner in HGSOC: implications for metabolism, stemness, and progression. In Cell death & disease, 15, 872. doi:10.1038/s41419-024-07257-6. https://pubmed.ncbi.nlm.nih.gov/39617776/

7. Liu, Dabin, Wong, Chi Chun, Fu, Li, Sung, Joseph J Y, Yu, Jun. . Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. In Science translational medicine, 10, . doi:10.1126/scitranslmed.aap9840. https://pubmed.ncbi.nlm.nih.gov/29669855/