https://scholars.lib.ntu.edu.tw/handle/123456789/160333
Title: | KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination | Authors: | Chen, H. Y. Hu, J. Y. Chen, T. H. Lin, Y. C. Liu, X. Lin, M. Y. Lang, Y. D. Yen, Y. Chen, R. H. |
Issue Date: | 2015 | Start page/Pages: | 5141-5151 | Source: | Oncogene | Abstract: | Cullin 3 (Cul3)-family ubiquitin ligases use the BTB-domain-containing proteins for the recruitment of substrates, but the regulation of this family of ubiquitin ligases has not been completely understood. KLHL20 is a BTB-family protein and targets tumor suppressor promyelocytic leukemia protein (PML) and death-associated protein kinase (DAPK) to its kelch-repeat domain for ubiquitination and degradation. Here, we show that another BTB-kelch protein KLHL39 is recruited to the substrate-binding domain of KLHL20 but is not a substrate of Cul3-KLHL20 complex. Interestingly, KLHL39 does not bind Cul3 because of the absence of certain conserved residues in the BTB domain. Instead, KLHL39 blocks KLHL20-mediated ubiquitination of PML and DAPK by disrupting the binding of these substrates to KLHL20 as well as the binding of KLHL20 to Cul3. Through the two mechanisms, KLHL39 increases the stability of PML and DAPK. In human colon cancers, downregulations of KLHL39, PML and DAPK are associated with metastatic progression. Furthermore, preclinical data indicate that KLHL39 promotes colon cancer migration, invasion and survival in vitro and metastasis in vivo through a PML- and DAPK-dependent mechanism. Our study identifies KLHL39 as a negative regulator of Cul3-KLHL20 ubiquitin ligase and reveals a role of KLHL39-mediated PML and DAPK stabilization in colon cancer metastasis. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/279012 | DOI: | 10.1038/onc.2014.435 | SDG/Keyword: | [SDGs]SDG3 binding protein; cullin 3; death associated protein kinase; KLHL20 protein; KLHL39 protein; Myc protein; promyelocytic leukemia protein; ubiquitin protein ligase; unclassified drug; carrier protein; DAPK1 protein, human; death associated protein kinase; IVNS1ABP protein, human; KLHL20 protein, human; nuclear protein; PML protein, human; transcription factor; tumor suppressor protein; anoikis; Article; cancer resistance; cell migration; colon cancer; controlled study; down regulation; female; HeLa cell line; human; human cell; immunohistochemistry; immunoprecipitation; in vivo study; metastasis; priority journal; protein degradation; protein expression; protein interaction; tumor invasion; ubiquitination; animal; colon tumor; genetic transfection; metabolism; metastasis; mouse; nude mouse; pathology; RNA interference; tissue microarray; tumor cell line; ubiquitination; xenograft; Animals; Carrier Proteins; Cell Line, Tumor; Colonic Neoplasms; Death-Associated Protein Kinases; Female; Heterografts; Humans; Immunohistochemistry; Immunoprecipitation; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Nuclear Proteins; RNA Interference; Tissue Array Analysis; Transcription Factors; Transfection; Tumor Suppressor Proteins; Ubiquitination |
Appears in Collections: | 分子醫學研究所 |
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