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Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism
CDC-like kinase 3 (CLK3) is a dual specificity kinase that functions on substrates containing serine/threonine and tyrosine. But its role in human cancer remains unknown. Herein, we demonstrated that CLK3 was significantly up-regulated in cholangiocarcinoma (CCA) and identified a recurrent Q607R som...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398168/ https://www.ncbi.nlm.nih.gov/pubmed/32453420 http://dx.doi.org/10.1084/jem.20191779 |
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author | Zhou, Qingxin Lin, Meihua Feng, Xing Ma, Fei Zhu, Yuekun Liu, Xing Qu, Chao Sui, Hong Sun, Bei Zhu, Anlong Zhang, Heng Huang, He Gao, Zhi Zhao, Yongxiang Sun, Jiangyun Bai, Yuxian Jin, Junfei Hong, Xuehui Zou, Chang Zhang, Zhiyong |
author_facet | Zhou, Qingxin Lin, Meihua Feng, Xing Ma, Fei Zhu, Yuekun Liu, Xing Qu, Chao Sui, Hong Sun, Bei Zhu, Anlong Zhang, Heng Huang, He Gao, Zhi Zhao, Yongxiang Sun, Jiangyun Bai, Yuxian Jin, Junfei Hong, Xuehui Zou, Chang Zhang, Zhiyong |
author_sort | Zhou, Qingxin |
collection | PubMed |
description | CDC-like kinase 3 (CLK3) is a dual specificity kinase that functions on substrates containing serine/threonine and tyrosine. But its role in human cancer remains unknown. Herein, we demonstrated that CLK3 was significantly up-regulated in cholangiocarcinoma (CCA) and identified a recurrent Q607R somatic substitution that represented a gain-of-function mutation in the CLK3 kinase domain. Gene ontology term enrichment suggested that high CLK3 expression in CCA patients mainly was associated with nucleotide metabolism reprogramming, which was further confirmed by comparing metabolic profiling of CCA cells. CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes. Notably, the CCA-associated CLK3-Q607R mutant induced USP13-Y708 phosphorylation and enhanced the activity of c-Myc. In turn, c-Myc transcriptionally up-regulated CLK3. Finally, we identified tacrine hydrochloride as a potential drug to inhibit aberrant CLK3-induced CCA. These findings demonstrate that CLK3 plays a crucial role in CCA purine metabolism, suggesting a potential therapeutic utility. |
format | Online Article Text |
id | pubmed-7398168 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-73981682021-02-03 Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism Zhou, Qingxin Lin, Meihua Feng, Xing Ma, Fei Zhu, Yuekun Liu, Xing Qu, Chao Sui, Hong Sun, Bei Zhu, Anlong Zhang, Heng Huang, He Gao, Zhi Zhao, Yongxiang Sun, Jiangyun Bai, Yuxian Jin, Junfei Hong, Xuehui Zou, Chang Zhang, Zhiyong J Exp Med Article CDC-like kinase 3 (CLK3) is a dual specificity kinase that functions on substrates containing serine/threonine and tyrosine. But its role in human cancer remains unknown. Herein, we demonstrated that CLK3 was significantly up-regulated in cholangiocarcinoma (CCA) and identified a recurrent Q607R somatic substitution that represented a gain-of-function mutation in the CLK3 kinase domain. Gene ontology term enrichment suggested that high CLK3 expression in CCA patients mainly was associated with nucleotide metabolism reprogramming, which was further confirmed by comparing metabolic profiling of CCA cells. CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes. Notably, the CCA-associated CLK3-Q607R mutant induced USP13-Y708 phosphorylation and enhanced the activity of c-Myc. In turn, c-Myc transcriptionally up-regulated CLK3. Finally, we identified tacrine hydrochloride as a potential drug to inhibit aberrant CLK3-induced CCA. These findings demonstrate that CLK3 plays a crucial role in CCA purine metabolism, suggesting a potential therapeutic utility. Rockefeller University Press 2020-05-26 /pmc/articles/PMC7398168/ /pubmed/32453420 http://dx.doi.org/10.1084/jem.20191779 Text en © 2020 Zhou et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Zhou, Qingxin Lin, Meihua Feng, Xing Ma, Fei Zhu, Yuekun Liu, Xing Qu, Chao Sui, Hong Sun, Bei Zhu, Anlong Zhang, Heng Huang, He Gao, Zhi Zhao, Yongxiang Sun, Jiangyun Bai, Yuxian Jin, Junfei Hong, Xuehui Zou, Chang Zhang, Zhiyong Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism |
title | Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism |
title_full | Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism |
title_fullStr | Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism |
title_full_unstemmed | Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism |
title_short | Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism |
title_sort | targeting clk3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398168/ https://www.ncbi.nlm.nih.gov/pubmed/32453420 http://dx.doi.org/10.1084/jem.20191779 |
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