Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism
Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism
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靶向 CLK3 通过重编程核苷酸代谢抑制胆管癌的进展
DOI：
10.1084/jem.20191779
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发表时间：
2020-08-01
影响因子：
15.3
通讯作者：
Zhang, Zhiyong
中科院分区：
文献类型：
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作者：
Zhou, Qingxin;Lin, Meihua;Zhang, Zhiyong
CDC样激酶3（CLK 3）是在含有丝氨酸/苏氨酸和酪氨酸的底物上起作用的双特异性激酶。但它在人类癌症中的作用仍然未知。在此，我们证明了CLK 3在胆管癌（CCA）中显著上调，并确定了一个复发性Q607 R体细胞置换，代表了CLK 3激酶结构域中的功能获得性突变。基因本体论术语富集提示CCA患者中CLK 3的高表达主要与核苷酸代谢重编程有关，这一点通过比较CCA细胞的代谢谱得到进一步证实。CLK 3直接磷酸化USP 13的Y 708，促进其与c-Myc的结合，从而阻止Fbxl 14介导的c-Myc泛素化并激活嘌呤代谢基因的转录。值得注意的是，CCA相关的CLK 3-Q607 R突变体诱导USP 13-Y 708磷酸化并增强c-Myc的活性。反过来，c-Myc转录上调CLK 3。最后，我们确定了盐酸他克林作为一种潜在的药物，以抑制异常的CLK 3诱导的CCA。这些发现表明，CLK 3在CCA嘌呤代谢中起着至关重要的作用，这表明了潜在的治疗用途。
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.