Cyclin-Dependent Kinase 5 (CDK5)-Mediated Phosphorylation of Upstream Stimulatory Factor 2 (USF2) Contributes to Carcinogenesis

Franklin, Tabughang; Horbach, Tina; Götz, Claudia; Kietzmann, Thomas; Dimova, Elitsa Y.

doi:10.3390/cancers11040523

Cited by 20 publications

(24 citation statements)

References 61 publications

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“…The current observations are also supported by studies in which depolarization of mitochondria occurred when CDK5, a positive regulator of USF2 [ 26 ], was knocked out [ 27 ]. Further, knockout of CDK5 in MDA MB-231 and MCF-7 cells enhanced ROS formation via mitochondria [ 27 ] in line with our present results showing an increased ROS formation in USF2-deficient cells.…”

Section: Discussionsupporting

confidence: 80%

“…gRNA-encoding oligonucleotides (Sigma-Aldrich) were cloned into the vector SpCas9(BB)-2A-GFP (PX458, Addgene plasmid ID 48138) using standard procedures as described [ 38 ]. The generation of the USF2 control and knockout cells via CRISPR-Cas9-mediated non-homologous end-joining (NHEJ) DNA repair and the screening of the clonal cell lines was performed as already described [ 26 , 39 ]. All primer sequences are listed in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

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Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner

et al. 2020

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The upstream stimulatory factor 2 (USF2) is a transcription factor implicated in several cellular processes and among them, tumor development seems to stand out. However, the data with respect to the role of USF2 in tumor development are conflicting suggesting that it acts either as tumor promoter or suppressor. Here we show that absence of USF2 promotes proliferation and migration. Thereby, we reveal a previously unknown function of USF2 in mitochondrial homeostasis. Mechanistically, we demonstrate that deficiency of USF2 promotes survival by inducing mitophagy in a ROS-sensitive manner by activating both ERK1/2 and AKT. Altogether, this study supports USF2′s function as tumor suppressor and highlights its novel role for mitochondrial function and energy homeostasis thereby linking USF2 to conditions such as insulin resistance, type-2 diabetes mellitus, and the metabolic syndrome.

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Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner

et al. 2020

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“…An increasing body of evidence supports that the cytoplasmic TF STAT3 is activated constitutively in a variety of cancers wherein it significantly affects the growth of tumors and facilitates metastasis [51,52]. USF2 is observed in various human cancers, plays important roles in embryogenesis, metabolism, and cancer development [53]. A previous study indicated that USF2 is associated with tumor grade and inversely with survival in Stage II colon cancers [54].…”

Section: Discussionmentioning

confidence: 99%

WGCNA reveals key gene modules regulated by the combined treatment of colon cancer with PHY906 and CPT11

Xing

Wang

et al. 2020

Bioscience Reports

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Irinotecan (CPT11) is one of the most effective drugs for treating colon cancer, but its severe side effects limit its application. Recently, a traditional Chinese herbal preparation, named PHY906, has been proved to be effective for improving therapeutic effect and reducing side effects of CPT11. The aim of this study was to provide novel insight to understand the molecular mechanism underlying PHY906-CPT11 intervention of colon cancer. Based on the GSE25192 dataset, for different three treatments (PHY906, CPT11, and PHY906-CPT11), we screened out differentially expressed genes (DEGs) and constructed a co-expression network by weighted gene co-expression network analysis (WGCNA) to identify hub genes. The key genes of the three treatments were obtained by merging the DEGs and hub genes. For the PHY906-CPT11 treatment, a total of 18 key genes including Eif4e, Prr15, Anxa2, Ddx5, Tardbp, Skint5, Prss12 and Hnrnpa3, were identified. The results of functional enrichment analysis indicated that the key genes associated with PHY906-CPT11 treatment were mainly enriched in “superoxide anion generation” and “complement and coagulation cascades”. Finally, we validated the key genes by GEPIA and RT-PCR analysis, the results indicated that EIF4E, PRR15, ANXA2, HNRNPA3, NCF1, C3AR1, PFDN2, RGS10, GNG11, and TMSB4X might play an important role in the treatment of colon cancer with PHY906-CPT11. In conclusion, a total of 18 key genes were identified in this study. These genes showed strong correlation with PHY906-CPT11 treatment in colon cancer, which may help elucidate the underlying molecular mechanism of PHY906-CPT11 treatment in colon cancer.

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“…In addition to proliferation, several studies reported that CDK5 plays a role in regulating cancer cell motility. Depending on the study, CDK5 was shown to promote migration of cancer cells by phosphorylating actin-binding/regulatory proteins such as caldesmon, talin, or FAK, phosphatidylinositol 4-phosphate 5-kinase type I γ (PIPKIγ90), PIKE-A, a transcription factor USF2, or to indirectly activate small GTP-ases RalA and RalB (11,50,51,(58)(59)(60)(61)(62)(63). In contrast, other authors concluded that CDK5 serves to inhibit cancer cell migration and to suppress metastasis by phosphorylating a tumor-suppressor DLC1, a scaffold protein muskelin, a transmembrane glycoprotein PDPN, an epigenetic regulator EZH2, or a protein phosphatase PP2A (64)(65)(66)(67)(68).…”

Section: Discussionmentioning

confidence: 99%

Targeting the cyclin-dependent kinase 5 in metastatic melanoma

Sharma

Zhang

Michowski

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.

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Cyclin-Dependent Kinase 5 (CDK5)-Mediated Phosphorylation of Upstream Stimulatory Factor 2 (USF2) Contributes to Carcinogenesis

Cited by 20 publications

References 61 publications

Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner

Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner

WGCNA reveals key gene modules regulated by the combined treatment of colon cancer with PHY906 and CPT11

Targeting the cyclin-dependent kinase 5 in metastatic melanoma

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