JMJD6 promotes colon carcinogenesis through negative regulation of p53 by hydroxylation

• Published in: PLoS biology 2014-03, Vol.12 (3), p.e1001819
• Main Authors: Wang, Feng, He, Lin, Huangyang, Peiwei, Liang, Jing, Si, Wenzhe, Yan, Ruorong, Han, Xiao, Liu, Shumeng, Gui, Bin, Li, Wanjin, Miao, Di, Jing, Chao, Liu, Zhihua, Pei, Fei, Sun, Luyang, Shang, Yongfeng
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Biology and Life Sciences; Cancer; Carcinogenesis - genetics; Cell cycle; Cell growth; Colon; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Female; Gene Expression Regulation, Neoplastic; Health aspects; Humans; Hydroxylation; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Jumonji Domain-Containing Histone Demethylases - physiology; Kinases; Male; Medicine and Health Sciences; Metastasis; Mice; Mice, Inbred BALB C; Middle Aged; Oncology, Experimental; Physiological aspects; Protein research; Retrospective Studies; Rodents; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1001819

Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.