Research group of CQU achieves important progress in research of new target of tumor treatment based on tumor suppressor p53 signal pathway

The research group led by Jiang Hui from the School of Bio-engineering of Chongqing University published their latest findings in the research of new intervention target of tumor treatment based on tumor suppressor p53 signal pathway in EBioMedicine, a sub-journal of The Lancet under the title “Zinc-finger protein p52-ZER6 accelerates colorectal cancer cell proliferation and tumour progression through promoting p53 ubiquitination” (doi: https://doi.org/10.1016/j.ebiom.2019.08.070) the other day. This research explored the molecular mechanism of tumor suppressor p53, and found a new target of clinical tumor therapy intervention targeting at tumor cell MDM2-p53 signal pathway. This research was the first to reveal the key role of p52-ZER6 protein, a shear of zinc finger protein ZER-6, in promoting the development of colorectal cancer, and further clarified that p52-ZER6 was able to significantly enhance the binding of tumor suppressor p53 protein with its upstream negative regulator MDM2, and facilitate the ubiquitination and degradation of p53 protein, thus leading to the proliferation disorder and deterioration of colon cancer cells. At present, inhibiting the binding of MDM2-p53 to promote the accumulation of p53 in tumor cells and induce the death of tumor cells was one of the focuses of clinical tumor drug research and development carried out by biopharmaceutical companies. In this Project, the research group found that the killing effect of such drugs targeting the MDM2-p53 signal pathway on tumor cells was closely related to the expression level of p52-ZER6 protein in cells. Based on the results of this study, the research group proposed that p52-ZER6 protein could be used as a new intervention target for colorectal cancer treatment; at the same time, it also provided a new strategy and theoretical guidance based on the expression level of p52-ZER6 protein in cells for the clinical tumor drug research and development of targeted MDM2-p53 complex inhibitor compounds currently being carried out by biopharmaceutical companies. Based on the research results, the research group has submitted two national invention patent applications, in hope of effectively promoting clinical translational medicine research through follow-up research and social cooperation.

Tumor suppressor p53 was the most studied tumor suppressor gene since it was discovered in 1979. P53 was considered to be the most important guardian of the genome. Its mutation and abnormal expression were quite common in cancer patients, and were closely related to tumor development. In cancer patients, the expression of p53 protein tended to decrease significantly, which would result in abnormal proliferation of tumor cells and death of cells able to bypass the cycle checkpoint. MDM2 was the upstream negative regulator of p53. It promoted the ubiquitination and degradation of p53 protein by binding with p53 protein. Therefore, one of the important strategies of clinical tumor treatment was to prevent the binding of MDM2 and p53 protein by targeting the MDM2-p53 signal pathway, so as to promote the functional recovery of p53 protein in tumor cells. It was also one of the focuses of the research and development of new clinical tumor drugs. In this research, we found that zinc-finger protein p52-ZER6 could enhance the combination of p53 protein and MDM2, promote the ubiquitination and degradation of p53 protein, significantly reduce the p53 protein in tumor cells, and ultimately lead to proliferation and significant increase in tumorigenic capacity of tumor cells. In addition, the research revealed that the expression of p52-ZER6 was abnormally increased in colon cancer patients, and the high expression of p52-ZER6 in tumor cells significantly reduced the inhibitory effect of Nutlin-family compounds, the MDM2-p53 binding complex inhibitor currently being developed, on tumor cell proliferation. Therefore, the research results not only provided new ideas for the research and development of tumor clinical drugs, but also provided important clinical guidance for the precise treatment of tumor.

Associate Professor Jiang Qihui from the School of Bio-engineering, Chongqing University, is the corresponding author of the paper. Huang Can, a doctoral student graduated in 2019 (now an associate professor of Anhui Medical University), is the first author of the paper. The research group led by Jiang Qihui mainly focused on the molecular mechanism of cell cycle regulation and tumor development, as well as the regulatory mechanism and function of tumor cell survival signal under tumor microenvironment. Recently, the research results of the research group on the role of YY1 in promoting the proliferation of hepatoma cells in tumor microenvironment by regulating lipid metabolism of hepatoma cells have also been published online in Theranostics, a biomedical journal (Li Yanjun, a doctoral candidate, as the first author, DOI: 10.7150/thno.34931, in press). In recent years, the research findings of the research group on cell cycle and tumorigenesis and development have been published as research papers in Science Advanced, Cancer Research and other international journals.

The research has been substantially supported by the Major Project of National Natural Science Foundation, General Project of National Natural Science Foundation, Chongqing Natural Science Foundation and Operating Expense for Basic Scientific Researches in Colleges and Universities Allocated by the Central Government; meanwhile, it has also been supported by the National Institute of Advanced Industrial Science and Technology of Japan and Chongqing Cancer Hospital. 

Link of the paper:

https://www.ebiomedicine.com/article/S2352-3964(19)30592-4/fulltext