Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma

• Published in: Cell reports (Cambridge) 2022-04, Vol.39 (3), p.110712-110712, Article 110712
• Main Authors: Shao, Wei-Qing, Zhu, Wen-Wei, Luo, Meng-Jun, Fan, Ming-Hao, Li, Qin, Wang, Sheng-Hao, Lin, Zhi-Fei, Zhao, Jing, Zheng, Yan, Dong, Qiong-Zhu, Lu, Lu, Jia, Hu-Liang, Zhang, Ju-Bo, Lu, Ming, Chen, Jin-Hong, Qin, Lun-Xiu
• Format: Article
• Language: English
• Subjects: Autophagy; Carcinoma, Hepatocellular - pathology; Cholesterol; cholesterol metabolism; Humans; liver cancer; Liver Neoplasms - pathology; lysosomal degradation; Membrane Proteins - metabolism; Receptor Protein-Tyrosine Kinases; statin; tyrosine kinase inhibitor
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110712

Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC. [Display omitted] •Cholesterol stabilizes RTKs in a GOLM1-dependent manner•GOLM1 mediates the selective autophagy of RTKs through a LIR motif•Cholesterol suppresses GOLM1-RTK degradation via mTORC1 pathway•Lowering cholesterol enhances the efficacy of multiple TKIs in HCC Aberrant activation of RTKs plays critical roles in cancer progression. Shao et al. find the importance of cholesterol as a signal to switch GOLM1-RTK degradation to its recycling. Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs via mTORC1 pathway. Lowering cholesterol by statins improves the efficacy of multiple TKIs in HCC by inducing RTK autophagy.