Recently, on the basis of the previous research on the interaction between protein ubiquitination and de ubiquitination (oncogene, 2020; iscence, 2019), the team of researcher Park Hailong from the biomolecular function and mechanism research group (1821 group) of Dalian Institute of chemistry, Chinese Academy of Sciences, the team of researcher Xu Guowang from the biomolecular high-resolution separation analysis and metabolomics research group (1808 group) and the team of Professor Tan Guang from the First Affiliated Hospital of Dalian Medical University cooperated, It is further found that the deubiquitinase USP22 can regulate the synthesis of lipid metabolism in liver cancer, and it is revealed that USP22 can activate the receptor through oxide enzyme proliferator γ （PPAR γ） The new mechanism of promoting fatty acid synthesis of liver cancer provides a new idea for the development of drugs targeting the lipid synthesis pathway of liver cancer.

Metabolic reprogramming is an important feature of cancer. Enhanced de novo synthesis of fatty acids is a common metabolic disorder in cancer cells. Normal cells mainly absorb and obtain lipids through exogenous sources, while cancer cells rely more on de novo synthesis of fatty acids to maintain lipid homeostasis, so as to meet the needs of their own proliferation and growth. Therefore, clearly targeting the fatty acid synthesis process of cancer cells is one of the important methods for the treatment of liver cancer.

In this work, by analyzing the expression of USP family proteins in liver cancer pathological tissues and combined with metabonomics, the researchers found that there was a significant correlation between deubiquitinase USP22 and liver cancer lipid synthesis; Subsequently, PPAR was further confirmed by cell and molecular biology experiments and metabolite analysis γ USP22 is an important substrate molecule involved in lipid metabolism of liver cancer. PPAR γ It is a ligand activated transcription factor, which can activate the expression of key enzymes of fatty acid synthesis, such as ACC, acly and FASN, and then promote lipid production. However, the current research on its regulation mechanism is not perfect. Through biochemical experiments, the researchers confirmed that USP22 can remove PPAR γ K48 ubiquitin chain of multiple lysine sites to stabilize its expression and stably express PPAR γ It will further activate the expression of its target genes ACC and acly, and finally promote the de novo synthesis of fatty acids and lead to the occurrence of liver cancer. In addition, the research team confirmed the interference of usp22-ppar through the study of mouse model γ- ACC / acly signal transduction pathway can not only inhibit lipid synthesis, but also significantly inhibit the growth of tumor in nude mice. USP22 and PPAR in clinical tissue γ、 The expression of ACC and acly had significant positive correlation. The prognosis of liver cancer patients with high expression of USP22 was poor. This work provides a new scientific basis for the treatment of targeted fatty acid synthesis of liver cancer.

Relevant research results are listed in “USP22 regulations lipidome accumulation by stabilizing PPAR” γ It was recently published in nature communications. The co first authors of this work are Ning Zhen, a postdoctoral in group 1808, Liu Xiaolong, an assistant researcher in group 1821, and Guo Xin and Lu Chang, doctoral graduates of Dalian Institute of Chemical Physics, Chinese Academy of Sciences. The above work has been supported by the National Natural Science Foundation of China, Liaoning Xingliao talent program, the innovation fund of Dalian Institute of Chemical Physics, Chinese Academy of Sciences, postdoctoral fund, youth promotion foundation of Chinese Academy of Sciences and other projects. (text / Liu Xiaolong / Ning Zhen)

Article link: https://doi.org/10.1038/s41467-022-29846-9