Absence of Scaffold Protein Tks4 Disrupts Several Signaling Pathways in Colon Cancer Cells

Jacksi, Mevan; Schád, Éva; Buday, László; Tantos, Ágnes

doi:10.3390/ijms24021310

Cited by 4 publications

(3 citation statements)

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“…The deletion of TKS4 generated numerous morphological alterations in the HCT116 cells, in keeping with the previously documented EMT-like characteristics [9,35]. To determine if there is a causal relationship between the observed morphological changes and the activation of EZH2, we applied an EZH2 activity inhibitor treatment.…”

Section: The Absence Of Tks4 Induces Migration and Emt-like Changes T...supporting

confidence: 60%

“…In our previous work [35], we demonstrated that the removal of TKS4 results in a fundamental reorganization of several different signaling pathways, which was accompanied by large-scale changes in the transcriptome of the TKS4 KO human colorectal cancer (HCT116) cells. In our pursuit to understand the molecular mechanisms behind these changes, our attention was drawn to EZH2, an important regulator of gene expression whose effects are similar to the phenotypic changes observed in the KO cells, and the Cancer Genome Atlas (TCGA) database revealed that the EZH2 expression was 2.4 times higher in colon cancer compared to normal cells [50].…”

Section: Elevation Of H3k27me3 In Tks4 Ko Cellsmentioning

confidence: 99%

“…Because of its recognized role in cancer progression, regulating EZH2 activity is considered an important anti-tumor therapeutic method [32][33][34]. Since TKS4 is not directly involved in gene expression regulation, the previous observations regarding the induction of EMT-like processes [9] and the dysregulation of a wide variety of signaling pathways upon the deletion of TKS4 [35] raise the possibility of an indirect mediator that conveys the removal of TKS4 into altered gene expression patterns. Based on the overlaps between the roles of EZH2 and the observed changes in the TKS4 KO cells, we hypothesized that this mediator may be EZH2 itself.…”

Section: Introductionmentioning

confidence: 99%

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Morphological Changes Induced by TKS4 Deficiency Can Be Reversed by EZH2 Inhibition in Colorectal Carcinoma Cells

Jacksi,

Schad,

Tantos

2024

Biomolecules

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Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phosphorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank–Ter Haar syndrome (FTHS). Based on our earlier investigation, the absence of TKS4 triggers migration, invasion, and epithelial–mesenchymal transition (EMT)-like phenomena while concurrently suppressing cell proliferation in HCT116 colorectal carcinoma cells. This indicates that TKS4 may play a unique role in the progression of cancer. In this study, we demonstrated that the enhancer of zeste homolog 2 (EZH2) and the histone methyltransferase of polycomb repressive complex 2 (PRC2) are involved in the migration, invasion, and EMT-like changes in TKS4-deficient cells (KO). EZH2 is responsible for the maintenance of the trimethylated lysine 27 on histone H3 (H3K27me3). Methods: We performed transcriptome sequencing, chromatin immunoprecipitation, protein and RNA quantitative studies, cell mobility, invasion, and proliferation studies combined with/without the EZH2 activity inhibitor 3-deazanoplanocine (DZNep). Results: We detected an elevation of global H3K27me3 levels in the TKS4 KO cells, which could be reduced with treatment with DZNep, an EZH2 inhibitor. Inhibition of EZH2 activity reversed the phenotypic effects of the knockout of TKS4, reducing the migration speed and wound healing capacity of the cells as well as decreasing the invasion capacity, while the decrease in cell proliferation became stronger. In addition, inhibition of EZH2 activity also reversed most epithelial and mesenchymal markers. We investigated the wider impact of TKS4 deletion on the gene expression profile of colorectal cancer cells using transcriptome sequencing of wild-type and TKS4 knockout cells, particularly before and after treatment with DZNep. Additionally, we observed changes in the expression of several protein-coding genes and long non-coding RNAs that showed a recovery in expression levels following EZH2 inhibition. Conclusions: Our results indicate that the removal of TKS4 causes a notable disruption in the gene expression pattern, leading to the disruption of several signal transduction pathways. Inhibiting the activity of EZH2 can restore most of these transcriptomics and phenotypic effects in colorectal carcinoma cells.

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Section: The Absence Of Tks4 Induces Migration and Emt-like Changes T...supporting

confidence: 60%

Section: Elevation Of H3k27me3 In Tks4 Ko Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Morphological Changes Induced by TKS4 Deficiency Can Be Reversed by EZH2 Inhibition in Colorectal Carcinoma Cells

Jacksi,

Schad,

Tantos

2024

Biomolecules

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Unveiling epithelial plasticity regulation in lung cancer: Exploring the cross-talk among Tks4 scaffold protein partners

László,

Kurilla,

Tilajka

et al. 2024

MBoC

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The epithelial to mesenchymal transition (EMT) represents a hallmark event in the evolution of lung cancer. This work aims to study a recently described EMT-regulating protein,Tks4, and to explore its potential as a prognostic biomarker in non-small cell lung cancer (NSCLC). In this study, we used CRISPR/Cas9 method to knockout Tks4 to study its functional roles in invadopodia formation, migration, and regulation of EMT marker expressions and we identified Tks4-interacting proteins. Tks4-KO A549 cells exhibited an EMT-like phenotype characterized by elongated morphology and increased expression of EMT markers. Furthermore, analyses of a large-scale lung cancer database and a patient-derived tissue array data revealed that the Tks4 mRNA level was decreased in more aggressive lung cancer stages. To understand the regulatory role of Tks4 in lung cancer, we performed a Tks4-interactome analysis via Tks4 immunoprecipitation-mass spectroscopy on four different cell lines and identified CAPZA1 as a novel Tks4 partner protein. Thus, we propose that the absence of Tks4 leads to disruption of a connectome of multiple proteins and that the resulting undocking and likely mislocalization of signaling molecules impairs actin cytoskeleton rearrangement and activates EMT-like cell fate switches, both of which likely influence disease severity.

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Morphological Changes Induced by TKS4 Deficiency Can Be Reversed by EZH2 Inhibition

Jacksi,

Schad,

Tantos

2024

Preprint

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Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phos-phorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank-Ter Haar syndrome (FTHS). Based on our earlier investigation, the absence of TKS4 triggers migration, invasion, and epithelial-mesenchymal transition (EMT)-like phenomena while concurrently suppressing cell proliferation in HCT116 colorectal carcinoma cells. This indicates that TKS4 may play a unique role in the progression of cancer. In this study, we demonstrated that the enhancer of zeste homolog 2 (EZH2) and the histone methyltransferase of polycomb repressive complex 2 (PRC2) are involved in the migration, invasion, and EMT-like changes in TKS4-deficient cells (KO). EZH2 is responsible for the maintenance of the trimethylated lysine 27 on histone H3 (H3K27me3). Methods: We performed the transcriptome sequencing, chromatin immunoprecipitation, protein and RNA quantitative studies, cell mobility, invasion, and proliferation studies combined with/without EZH2 activity inhibitor 3-deazanoplanocine (DZNep) Results: We detected an elevation of global H3K27me3 levels in the TKS4 KO cells, which could be reduced with treatment with DZNep, an EZH2 inhibitor. Inhibition of EZH2 activity reversed the phenotypic effects of the knockout of TKS4, reducing the migration speed and wound healing capacity of the cells as well as decreasing the invasion capacity, while the decrease in cell prolif-eration became stronger. In addition, inhibition of EZH2 activity also reversed most epithelial and mesenchymal markers. We investigated the wider impact of TKS4 deletion on the gene expression profile of colorectal cancer cells using transcriptome sequencing of wild-type and TKS4 knockout cells, particularly before and after treatment with DZNep. Additionally, we observed changes in the expression of several protein-coding genes and long non-coding RNAs that showed a recovery in expression levels following EZH2 inhibition. Conclusions: Our results indicate that the removal of TKS4 causes a notable disruption in the gene expression pattern, leading to the disruption of several signal transduction pathways. Inhibiting the activity of EZH2 can restore most of these transcriptomics and phenotypic effects.

show abstract

Absence of Scaffold Protein Tks4 Disrupts Several Signaling Pathways in Colon Cancer Cells

Cited by 4 publications

References 123 publications

Morphological Changes Induced by TKS4 Deficiency Can Be Reversed by EZH2 Inhibition in Colorectal Carcinoma Cells

Morphological Changes Induced by TKS4 Deficiency Can Be Reversed by EZH2 Inhibition in Colorectal Carcinoma Cells

Unveiling epithelial plasticity regulation in lung cancer: Exploring the cross-talk among Tks4 scaffold protein partners

Morphological Changes Induced by TKS4 Deficiency Can Be Reversed by EZH2 Inhibition

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