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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
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.
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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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