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.

Glycogen accumulation and phase separation drives liver tumor initiation through blocking Hippo signaling

A research paper based on the results titled “Glycogen accumulation and phase separation drives liver tumor initiation” was published on the Cell website on 21 October 2021. Co-first authors of the paper are PhD students including Liu Qingxu, Li Jiaxin, Zhang Weiji, and Xiao Chen and Postdoc Researcher Zhang Shihao. Prof. Zhou Dawang and Prof. Chen Lanfen of Xiamen University are the co-corresponding authors of the paper. The research gained support from National Key Research and Development Program of China, National Natural Science Foundation of China, the 111 Project and the Fundamental Research Funds for the Central Universities of China-Xiamen University.

This paper pays special tribute to Mr. Qingxu Liu, one of the first authors, who sadly passed away on June 11th, 2020 as a result of Non-Hodgkin lymphoma. He had signed up through the Red Cross Society of China to donate his body to the University’s medical school, for the use of scientific research and education. Liu Qingxu played a vital role in initiating this project and made several critical findings on his own.

Paper link: https://doi.org/10.1016/j.cell.2021.10.001