Glycogen accumulation and phase separation drives liver tumor initiation
| Autor: | Hui Shao, Cheng Nian, Dawang Zhou, Jing Geng, Jin Ding, Yuxi Li, Xianming Deng, Weiji Zhang, Hao Zhao, Shuhai Lin, Chen Xiao, Lihong Chen, Qian Zhao, Randy L. Johnson, Shihao Zhang, Qingxu Liu, Xiaolong Liu, Dongxue Su, Lixin Hong, Qinghua Chen, Junhong Li, Qiao Wu, Lanfen Chen, Jiaxin Li, Rongqin Ke |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male G6PC Glycogenolysis Carcinogenesis Down-Regulation Biology Serine-Threonine Kinase 3 General Biochemistry Genetics and Molecular Biology Phase Transition Malignant transformation Cell Line chemistry.chemical_compound Glycogen phosphorylase Proto-Oncogene Proteins medicine Glycogen storage disease Animals Humans Hippo Signaling Pathway Aged Neoplasm Staging Aged 80 and over Mice Knockout Glycogen Kinase Hepatocyte Growth Factor Glycogen Phosphorylase Liver Neoplasms YAP-Signaling Proteins Middle Aged medicine.disease Protein Tyrosine Phosphatases Non-Receptor Cell biology Gene Expression Regulation Neoplastic Mice Inbred C57BL Disease Models Animal chemistry Liver Hippo signaling Glucose-6-Phosphatase Female Precancerous Conditions |
| Zdroj: | Cell. 184(22) |
| ISSN: | 1097-4172 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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