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Glycogen accumulation and phase separation drives liver tumor initiation
Cell  (IF41.582),  Pub Date : 2021-10-21, DOI: 10.1016/j.cell.2021.10.001
Qingxu Liu, Jiaxin Li, Weiji Zhang, Chen Xiao, Shihao Zhang, Cheng Nian, Junhong Li, Dongxue Su, Lihong Chen, Qian Zhao, Hui Shao, Hao Zhao, Qinghua Chen, Yuxi Li, Jing Geng, Lixin Hong, Shuhai Lin, Qiao Wu, Dawang Zhou

Glucose consumption is generally increased in tumor cells to support tumor growth. Interestingly, we report that glycogen accumulation is a key initiating oncogenic event during liver malignant transformation. We found that glucose-6-phosphatase (G6PC) catalyzing the last step of glycogenolysis is frequently downregulated to augment glucose storage in pre-malignant cells. Accumulated glycogen undergoes liquid-liquid phase separation, which results in the assembly of the Laforin-Mst1/2 complex and consequently sequesters Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme-liver glycogen phosphorylase (PYGL) deficiency in both human and mice results in glycogen storage disease along with liver enlargement and tumorigenesis in a Yap-dependent manner. Consistently, elimination of glycogen accumulation abrogates liver growth and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that cancer-initiating cells adapt a glycogen storing mode, which blocks Hippo signaling through glycogen phase separation to augment tumor incidence.