KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination

H. Y. Chen, J. Y. Hu, T. H. Chen, Y. C. Lin, X. Liu, M. Y. Lin, Y. D. Lang, Y. Yen, R. H. Chen

研究成果: 雜誌貢獻文章

14 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)5141-5151
頁數11
期刊Oncogene
34
發行號40
DOIs
出版狀態已發佈 - 十月 1 2015

指紋

Death-Associated Protein Kinases
Cullin Proteins
Ubiquitination
Colonic Neoplasms
Neoplasm Metastasis
Ligases
Ubiquitin
Tumor Suppressor Proteins
Proteins
Promyelocytic Leukemia Protein
Down-Regulation
Survival

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

引用此文

Chen, H. Y., Hu, J. Y., Chen, T. H., Lin, Y. C., Liu, X., Lin, M. Y., ... Chen, R. H. (2015). KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination. Oncogene, 34(40), 5141-5151. https://doi.org/10.1038/onc.2014.435

KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination. / 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.

於: Oncogene, 卷 34, 編號 40, 01.10.2015, p. 5141-5151.

研究成果: 雜誌貢獻文章

Chen, HY, Hu, JY, Chen, TH, Lin, YC, Liu, X, Lin, MY, Lang, YD, Yen, Y & Chen, RH 2015, 'KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination', Oncogene, 卷 34, 編號 40, 頁 5141-5151. https://doi.org/10.1038/onc.2014.435
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. / KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination. 於: Oncogene. 2015 ; 卷 34, 編號 40. 頁 5141-5151.
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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.",
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AU - Chen, H. Y.

AU - Hu, J. Y.

AU - Chen, T. H.

AU - Lin, Y. C.

AU - Liu, X.

AU - Lin, M. Y.

AU - Lang, Y. D.

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AB - 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.

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