Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism.

Abstract

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.

• Authors: Qingxin Zhou, Meihua Lin, Xing Feng, Fei Ma, Yuekun Zhu, Xing Liu, Chao Qu, Hong Sui, Bei Sun, Anlong Zhu, Heng Zhang, He Huang, Zhi Gao, Yongxiang Zhao, Jiangyun Sun, Yuxian Bai, Junfei Jin, Xuehui Hong, Chang Zou, Zhiyong Zhang
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 217 Issue 8 (08 03 2020) ISSN: 1540-9538 [Electronic] United States
• PMID: 32453420 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Zhou et al.

Chemical References

• Neoplasm Proteins
• Purines
• Tacrine
• Clk dual-specificity kinases
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• purine

Topics

• Amino Acid Substitution
• Bile Duct Neoplasms (drug therapy, enzymology, genetics)
• Cell Line, Tumor
• Cellular Reprogramming (drug effects)
• Cholangiocarcinoma (drug therapy, enzymology, genetics)
• Drug Delivery Systems
• Gain of Function Mutation
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Mutation, Missense
• Neoplasm Proteins (biosynthesis, genetics)
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors, biosynthesis, genetics)
• Protein-Tyrosine Kinases (antagonists & inhibitors, biosynthesis, genetics)
• Purines (metabolism)
• Tacrine (pharmacology)
• Up-Regulation (drug effects)