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Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism
Qingxin Zhou1,2,3, Meihua Lin4,5, Xing Feng6
1The Affiliated Hospital of Guilin Medical University, Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guangxi Neurological Diseases Clinical Research Center, Guilin, Guangxi, China.
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.
Insights
CDC-like kinase 3 (CLK3) is upregulated in cholangiocarcinoma (CCA), driving purine metabolism changes. A gain-of-function mutation enhances this activity, suggesting CLK3 as a therapeutic target for CCA.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- CDC-like kinase 3 (CLK3) is a dual specificity kinase with an uncharacterized role in human cancer.
- Cholangiocarcinoma (CCA) is a complex malignancy with limited therapeutic options.
Purpose of the Study:
- To investigate the role of CLK3 in cholangiocarcinoma (CCA).
- To elucidate the molecular mechanisms by which CLK3 influences CCA progression.
- To identify potential therapeutic strategies targeting CLK3 in CCA.
Main Methods:
- Gene expression analysis in CCA tissues.
- Somatic mutation analysis of the CLK3 kinase domain.
- Gene ontology and metabolic profiling of CCA cells.
- In vitro kinase assays and protein interaction studies.
- Assessment of drug efficacy in preclinical models.
Main Results:
- CLK3 is significantly upregulated in CCA, with a recurrent Q607R gain-of-function mutation identified.
- High CLK3 expression correlates with nucleotide metabolism reprogramming in CCA.
- CLK3 directly phosphorylates USP13, enhancing c-Myc stability and activating purine metabolic genes.
- The CLK3-Q607R mutant shows increased activity and promotes c-Myc-mediated CLK3 transcription.
- Tacrine hydrochloride demonstrates potential as an inhibitor of CLK3 in CCA.
Conclusions:
- CLK3 plays a critical role in regulating purine metabolism in CCA.
- Aberrant CLK3 activity, particularly the Q607R mutant, contributes to CCA pathogenesis.
- Targeting CLK3 with agents like tacrine hydrochloride offers a potential therapeutic avenue for CCA.
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