Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism

Zhou, Qingxin1,2,3; Lin, Meihua4,5; Feng, Xing6; Ma, Fei7; Zhu, Yuekun8,9; Liu, Xing10; Qu, Chao11; Sui, Hong2; Sun, Bei8,9; Zhu, Anlong8; Zhang, Heng12; Huang, He12; Gao, Zhi13; Zhao, Yongxiang13; Sun, Jiangyun14; Bai, Yuxian2; Jin, Junfei15,16; Hong, Xuehui17; Zou, Chang18,19; Zhang, Zhiyong1,20

2020-08

10.1084/jem.20191779

JOURNAL OF EXPERIMENTAL MEDICINE   影响因子和分区

0022-1007

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.

SCI

英语

NI期刊

通讯

National Natural Science Foundation of China[81702387][81702744][81960520] ; Science and Technology Planned Project in Guilin[20190206-1] ; Guangxi Distinguished Experts Special Fund[2019-13-12] ; Natural Science Foundation of Fujian Province[2017J01368][2017J01369] ; Training Program for Young Talents of Fujian Health System[2016-ZQN-85] ; Fujian Provincial Funds for Distinguished Young Scientists[2018D0016] ; Fujian Health Education Joint Research Project[WKJ2016-2-17] ; Heilongjiang Postdoctoral Science Foundation[LBH-Z17176] ; Science and Technology Foundation of Shenzhen[JCYJ20170412155231633][JCYJ20180305164128430] ; Shenzhen Economic and Information Committee "Innovation Chain and Industry Chain" integration special support plan project[20180225112449943]

Immunology ; Research & Experimental Medicine

Immunology ; Medicine, Research & Experimental

WOS:000575157300006

ROCKEFELLER UNIV PRESS

IMMUNOLOGY

Web of Science

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Zhou, Qingxin,Lin, Meihua,Feng, Xing,et al. Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism[J]. JOURNAL OF EXPERIMENTAL MEDICINE,2020,217(8).

Zhou, Qingxin.,Lin, Meihua.,Feng, Xing.,Ma, Fei.,Zhu, Yuekun.,...&Zhang, Zhiyong.(2020).Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism.JOURNAL OF EXPERIMENTAL MEDICINE,217(8).

Zhou, Qingxin,et al."Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism".JOURNAL OF EXPERIMENTAL MEDICINE 217.8(2020).