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学科主题: 基础医学
题名:
JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by Hydroxylation
作者: Wang, Feng1; He, Lin1; Huangyang, Peiwei1; Liang, Jing1; Si, Wenzhe1,2; Yan, Ruorong1; Han, Xiao1; Liu, Shumeng1; Gui, Bin1; Li, Wanjin1; Miao, Di3; Jing, Chao4; Liu, Zhihua4; Pei, Fei5; Sun, Luyang1; Shang, Yongfeng1,2
刊名: PLOS BIOLOGY
发表日期: 2014-03-01
DOI: 10.1371/journal.pbio.1001819
卷: 12, 期:3
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Biology
研究领域[WOS]: Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics
关键词[WOS]: DAMAGE-INDUCED PHOSPHORYLATION ; UBIQUITIN-PROTEIN LIGASE ; DNA-DAMAGE ; PHOSPHATIDYLSERINE RECEPTOR ; BREAST-CANCER ; HISTONE MODIFICATION ; TUMOR-SUPPRESSOR ; APOPTOTIC CELLS ; MDM2 ; ACETYLATION
英文摘要:

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 -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 G(1) 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.

Author Summary JMJD6 belongs to the Jumonji C domain-containing family of proteins. The majority of this family are histone demethylases implicated in chromatin-associated events, but there have also been some reports of lysyl hydroxylase activity for JMJD6. Here we report a new posttranslational modification for the tumor suppressor protein p53 that is mediated by JMJD6. Via a physical associations with p53, JMJD6 catalyzes the hydroxylation of p53, thereby repressing its transcriptional activity. Depletion of JMJD6 promotes cell apoptosis, arrests cells in the G1 phase, sensitizes cells to DNA damaging agent-induced cell death, and represses p53-dependent colon cell proliferation and tumorigenesis. 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 support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.

语种: 英语
所属项目编号: 91219201 ; 81130048 ; 81071673 ; 81372223 ; 2011CB504204 ; 2014CB542004
项目资助者: National Natural Science Foundation of China ; Ministry of Science and Technology of China
WOS记录号: WOS:000333406800001
Citation statistics:
内容类型: 期刊论文
版本: 出版稿
URI标识: http://ir.bjmu.edu.cn/handle/400002259/59581
Appears in Collections:基础医学院_病理学系_期刊论文

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作者单位: 1.Peking Univ, Dept Biochem & Mol Biol, Key Lab Carcinogenesis & Translat Res, Minist Educ,Sci Ctr, Beijing 100871, Peoples R China
2.Tianjin Med Univ, Dept Biochem & Mol Biol, Collaborat Innovat Ctr Tianjin Med Epigenet 2011, Tianjin Key Lab Med Epigenet, Tianjin, Peoples R China
3.Tsinghua Univ, Prote Facil, Sch Life Sci, Beijing 100084, Peoples R China
4.Chinese Acad Med Sci, Inst Canc, Peking Union Med Coll, State Key Lab Mol Oncol, Beijing 100021, Peoples R China
5.Peking Univ, Dept Pathol, Hlth Sci Ctr, Beijing 100871, Peoples R China

Recommended Citation:
Wang, Feng,He, Lin,Huangyang, Peiwei,et al. JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by Hydroxylation[J]. PLOS BIOLOGY,2014,12(3).
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