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, Aiguo; Zhang, Heng; Huang, He; Gao, Zhi; Zhao, Yongxiang; Sun, Jiangyun; Bai, Yuxian; Jin, Junfei; Hong, Xuehui; Zou, Chang; Zhang, Zhiyong

doi:10.1084/jem.20191779

Cited by 47 publications

(49 citation statements)

References 31 publications

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“…CLK3 contributes to hepatocellular carcinoma [ 226 ], prostate cancer [ 227 ], and cholangiocarcinoma [ 228 ]. CLK3 is abundantly expressed in testis and in spermatozoa.…”

Section: Clks and Human Diseasementioning

confidence: 99%

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Lindberg

Meijer

2021

IJMS

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Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

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“…CLK3 contributes to hepatocellular carcinoma [ 226 ], prostate cancer [ 227 ], and cholangiocarcinoma [ 228 ]. CLK3 is abundantly expressed in testis and in spermatozoa.…”

Section: Clks and Human Diseasementioning

confidence: 99%

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Lindberg

Meijer

2021

IJMS

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“…Moreover, a recent study also found that CDC-like kinase 3 (CLK3) or the cholangiocarcinoma-associated CLK3-Q607R mutant can directly phosphorylate USP13 at Tyr708, and promote its binding to c-Myc (Nayler et al, 1997;Zhou et al, 2020) (Figure 3B). Therefore, this stabilizes c-Myc and activates the transcription of genes related to purine metabolism (Figure 3B).…”

Section: Phosphorylation Regulates the Interactome And Localization Of Dubsmentioning

confidence: 88%

Post-Translational Modifications of Deubiquitinating Enzymes: Expanding the Ubiquitin Code

Wang

2021

Front. Pharmacol.

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Post-translational modifications such as ubiquitination play important regulatory roles in several biological processes in eukaryotes. This process could be reversed by deubiquitinating enzymes (DUBs), which remove conjugated ubiquitin molecules from target substrates. Owing to their role as essential enzymes in regulating all ubiquitin-related processes, the abundance, localization, and catalytic activity of DUBs are tightly regulated. Dysregulation of DUBs can cause dramatic physiological consequences and a variety of disorders such as cancer, and neurodegenerative and inflammatory diseases. Multiple factors, such as transcription and translation of associated genes, and the presence of accessory domains, binding proteins, and inhibitors have been implicated in several aspects of DUB regulation. Beyond this level of regulation, emerging studies show that the function of DUBs can be regulated by a variety of post-translational modifications, which significantly affect the abundance, localization, and catalytic activity of DUBs. The most extensively studied post-translational modification of DUBs is phosphorylation. Besides phosphorylation, ubiquitination, SUMOylation, acetylation, oxidation, and hydroxylation are also reported in DUBs. In this review, we summarize the current knowledge on the regulatory effects of post-translational modifications of DUBs.

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“…Briefly, GC cells with the indicated lentivirus expression plasmid against miR-148b-5p or negative control (scramble) were subcutaneously injected into the flanks of nude mice. After seven weeks, the nude mice were killed through cervical dislocation, and the tumors were measured, and experiments such as western blots and IHC were performed as described previously ( 11 ).…”

Section: Methodsmentioning

confidence: 99%

Targeting miR-148b-5p Inhibits Immunity Microenvironment and Gastric Cancer Progression

et al. 2021

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BackgroundMicroRNAs (miRNAs) have been discovered to dictate the development of various tumors. However, studies on the roles of miRNAs in the progression of gastric cancer (GC) are still lacking.MethodsHerein, by analyzing GC cell lines and patients samples, we observed that miR-148b-5p was significantly downregulated in GC. We also confirmed that miR-148b-5p overexpression significantly inhibited GC cell proliferation and invasion in vitro and in vivo.ResultsOverexpression of miR-148b-5p not only reprogrammed the metabolic properties of GC but also regulated the immune microenvironment by shifting lymphocyte and myeloid populations. Mechanistically, ATPIF1, an important glycolysis-associated gene, was identified as a direct target of miR-148b-5p and mediated the effect of miR-148b-5p. Notably, the low level of miR-148b-5p was significantly related with poor prognosis of GC patients (P < 0.001). Importantly, the levels of miR-148b-5p significantly changed the sensitivity of GC cells to several anti-cancer drugs (Doxorubicin, P < 0.05, Paclitaxel, P < 0.01, Docetaxel, P < 0.05).ConclusionsTargeting miR-148b-5p inhibits immunity microenvironment and gastric cancer progression.

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Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism

Cited by 47 publications

References 31 publications

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Post-Translational Modifications of Deubiquitinating Enzymes: Expanding the Ubiquitin Code

Targeting miR-148b-5p Inhibits Immunity Microenvironment and Gastric Cancer Progression

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