Demethylase-independent function of JMJD2D as a novel antagonist of p53 to promote Liver Cancer initiation and progression

Autor: Minghui Zhuo, Qiang Chen, Hui Zhou, Pingli Mo, Peng Guo, Chundong Yu, Xiaogang Xia, Ming Li, Wengang Li, Zhaojie Su, Yuan Deng, Xu Kong
Rok vydání: 2020
Předmět:
Cyclin-Dependent Kinase Inhibitor p21
Male
p53
0301 basic medicine
Jumonji Domain-Containing Histone Demethylases
Cell Survival
Colorectal cancer
Mice
Nude
Medicine (miscellaneous)
Biology
liver cancer
Mice
03 medical and health sciences
0302 clinical medicine
Cell Line
Tumor
Proto-Oncogene Proteins
PUMA
medicine
Animals
Humans
Wnt Signaling Pathway
Pharmacology
Toxicology and Pharmaceutics (miscellaneous)
Cell Proliferation
Gene knockdown
p21
Cell growth
JMJD2D
Liver Neoplasms
Wnt signaling pathway
Hep G2 Cells
Cell cycle
medicine.disease
Up-Regulation
Gene Expression Regulation
Neoplastic
030104 developmental biology
Apoptosis
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Disease Progression
Cancer research
Tumor Suppressor Protein p53
Signal transduction
Apoptosis Regulatory Proteins
Liver cancer
Neoplasm Transplantation
Research Paper
Zdroj: Theranostics
ISSN: 1838-7640
Popis: Background: As a histone demethylase, JMJD2D can enhance gene expression by specifically demethylating H3K9me2/3 and plays an important role in promoting colorectal cancer progression. However, its role in liver cancer remains unclear. Methods: The expression of JMJD2D was examined in human liver cancer specimens and non-tumorous liver tissues by immunohistochemical or immunoblot analysis. JMJD2D expression was knocked down in liver cancer cells using small hairpin RNAs, and cells were analyzed with Western blot, real-time PCR, cell viability, colony formation, and flow cytometry assays. Cells were also grown as tumor xenografts in nude mice, and the tumor cell proliferation and apoptosis were measured by immunohistochemical analysis. The relationship between JMJD2D and p53 was studied by co-immunoprecipitation, chromatin immunoprecipitation, and electric mobility shift assay. Wild-type and JMJD2D-knockout mice were intraperitoneally injected with diethylnitrosamine (DEN) to induce liver tumors and the liver cancer initiation and progression were investigated. Results: JMJD2D was frequently upregulated in human liver cancer specimens compared with non-tumorous liver tissues. The overall survival of liver cancer patients with high JMJD2D expression was significantly decreased compared to that with low JMJD2D expression. JMJD2D knockdown reduced liver cancer cell proliferation and xenograft tumor growth, sensitized cells to chemotherapeutic drug-induced apoptosis, and increased the expression of cell cycle inhibitor p21 and pro-apoptosis gene PUMA. Genetically, JMJD2D deficiency protected mice against DEN-induced liver cancer initiation and progression. Knockout of tumor suppressor p53 significantly reduced the effects of JMJD2D knockdown on cell proliferation, apoptosis, and the expression of p21 and PUMA, suggesting that JMJD2D regulates liver cancer cell functions in part through inhibiting p53 signaling pathway. Mechanistically, JMJD2D directly interacted with p53 and inhibited p53 recruitment to the p21 and PUMA promoters in a demethylation activity-independent manner, implicating a demethylase-independent function of JMJD2D as a novel p53 antagonist. In addition, JMJD2D could activate Wnt/β-catenin signaling to promote liver cancer cell proliferation. Conclusion: Our study demonstrates that JMJD2D can antagonize the tumor suppressor p53 and activate an oncogenic signaling pathway (such as Wnt/β-catenin signaling pathway) simultaneously to promote liver cancer initiation and progression, suggesting that JMJD2D may serve as a novel target for liver cancer treatment.
Databáze: OpenAIRE
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