Squalene epoxidase promotes hepatocellular carcinoma development by activating STRAP transcription and TGF‐β/SMAD signalling

• Published in: British journal of pharmacology 2023-06, Vol.180 (12), p.1562-1581
• Main Authors: Zhang, Zhirui, Wu, Wei, Jiao, Hao, Chen, Yuzhong, Ji, Xiaojun, Cao, Jing, Yin, Fangzhou, Yin, Wu
• Format: Article
• Language: English
• Subjects: Actin; Bioinformatics; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell growth; Cell Line; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Cholesterol; Drug development; Gene expression; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Humans; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Metastases; NB‐598; Ribonucleic acid; RNA; Smad protein; Squalene; Squalene epoxidase; Squalene Monooxygenase - genetics; Squalene Monooxygenase - metabolism; STRAP; TGF‐β/SMADs; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Wound healing
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.16024

Background and Purpose Squalene epoxidase (SQLE) is a key enzyme involved in cholesterol biosynthesis, but growing evidence also reveals that SQLE is abnormally expressed in some types of malignant tumours, even though the underlying mechanism remains poorly understood. Experimental Approach Bioinformatics analysis and RNA sequencing were applied to detect differentially expressed genes in clinical hepatocellular carcinoma (HCC). MTT, colony formation, AnnexinV‐FITC/PI, EdU, wound healing, transwell, western blot, qRT‐PCR, IHC, F‐actin, RNA‐sequencing, dual‐luciferase reporters, and H&E staining were used to investigate the pharmacological effects and possible mechanisms of SQLE. Key Results SQLE expression was specifically elevated in HCC, correlating with poor clinical outcomes. SQLE significantly promoted HCC growth, epithelial–mesenchymal transition, and metastasis both in vitro and in vivo. RNA sequencing and functional experiments revealed that the protumourigenic effect of SQLE on HCC was closely related to the activation of TGF‐β/SMAD signalling, but the stimulatory effect of SQLE on TGF‐β/SMAD signalling and HCC development is critically dependent on STRAP. SQLE expression is well correlated with STRAP in HCC, and further, to amplify TGF‐β/SMAD signalling, SQLE even transcriptionally increased STRAP gene expression mediated by AP‐2α. Finally, as a chemical inhibitor of SQLE, NB‐598 markedly inhibited HCC cell growth and tumour development. Conclusions and Implications Taken together, SQLE serves as a novel oncogene in HCC development by activating TGF‐β/SMAD signalling. Targeting SQLE could be useful in drug development and therapy for HCC.