The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma
Binhui Zhou, Ying Wang, Lichen Zhang, Xiaoyi Shi, Hesheng Kong, Mengjie Zhang, Yang Liu, Xia Shao, Zhilong Liu, Hongxu Song, Wushan Li, Xiaoxi Gao, Yanli Chang, Dou Chenzhuo, Wenzhi Guo, Shuijun Zhang, Xiaohong Kang, Jie Gao, Yinming Liang, Junfeng Zheng, Eryan Kong
Abstract
Rationale: Protein palmitoylation is tightly related to tumorigenesis or tumor progression as many oncogenes or tumor suppressors are palmitoylated. AEG-1, an oncogene, is commonly elevated in a variety of human malignancies, including hepatocellular carcinoma (HCC). Although AEG-1 was suggested to be potentially modified by protein palmitoylation, the regulatory roles of AEG-1 palmitoylation in tumor progression of HCC has not been explored. Methods: Techniques as Acyl-RAC assay and point mutation were used to confirm that AEG-1 is indeed palmitoylated. Moreover, biochemical experiments and immunofluorescent microscopy were applied to examine the cellular functions of AEG-1 palmitoylation in several cell lines. Remarkably, genetically modified knock-in (AEG-1-C75A) and knockout (Zdhhc6-KO) mice were established and subjected to the treatment of DEN to induce the HCC mice model, through which the roles of AEG-1 palmitoylation in HCC is directly addressed. Last, HCQ, a chemical compound, was introduced to prove in principal that elevating the level of AEG-1 palmitoylation might benefit the treatment of HCC in xenograft mouse model.