XMU Research Team Discovers Glycogen Accumulation and Phase Separation Driving Liver Tumor Initiation
Glycogen is the largest soluble cytosolic macromolecule and considered as the principal storage form of glucose. Glucose consumption is generally increased in advanced tumor cells to support tumor growth. Recently, Prof. Zhou Dawang and colleagues reported that glycogen accumulation is a key initiating oncogenic event, essential for liver malignant transformation. They found that glucose-6-phosphatase (G6PC), an enzyme catalyzing the last step of glycogenolysis, is frequently downregulated to augment glucose storage in pre-malignant cells. Accumulated glycogen undergoes liquid-liquid phase separation (LLPS), 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 result 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, they concluded that cancer initiating cells adapt glycogen storing mode which blocks Hippo signaling through glycogen phase separation to augment tumor incidence.