EZH2 as a potential therapeutic target for gastrointestinal cancers

Hashemi, Mehrdad; Nazdari, Naghmeh; Gholamiyan, Ghazaleh; Paskeh, Mahshid Deldar Abad; Jafari, Ali Moghadas; Nemati, Fateme; Khodaei, Elaheh; Abyari, Ghazal; behdadfar, Nazanin; Raei, Behnaz; Raesi, Rasoul; Nabavi, Noushin; Hu, Peng; Rashidi, Mohsen; Taheriazam, Afshin; Entezari, Maliheh

doi:10.1016/j.prp.2023.154988

Cited by 4 publications

(1 citation statement)

References 220 publications

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“…Overactivation is observed in several cancers [30,31], and higher EZH2 activity is generally accompanied by a worse disease prognosis and a more aggressive phenotype. 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.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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3-Deazaneplanocin A (DZNep): A Drug That Deserves a Second Look

Marquez

2024

J. Med. Chem.

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The emerging data compiled during the past five years on 3-deazaneplanocin (DZNep) provide compelling evidence to reevaluate this drug as a better alternative over the specific catalytic inhibitors of histone methyl transferases (HTMs). The indirect mechanism of DZNep via inhibition of AdoHcy-ase, once considered a liability due to possible side effects, has now shown to be rather beneficial as additional pathways targeted by DZNep are important contributors to its superior anticancer properties. Furthermore, DZNep has demonstrated the ability to induce proteasomal degradation of its target and reduce toxicity in combination with well-established antitumor therapies in animal models. In addition, DZNep has shown important effects in suppressing fibrosis and inflammation in liver, kidney, peritoneum, and airways. Finally, inhibition of mRNA m 6 A methylation by DZNep suppresses the synthesis of the viral genome in SARS-Cov-2 infection and promises to have important therapeutic value when combined with its potent antiviral efficacy and anti-inflammatory effects.

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Dual-target EZH2 inhibitor: latest advances in medicinal chemistry

Wei,

Mei,

et al. 2024

Future Medicinal Chemistry

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EZH2 as a potential therapeutic target for gastrointestinal cancers

Cited by 4 publications

References 220 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

3-Deazaneplanocin A (DZNep): A Drug That Deserves a Second Look

Dual-target EZH2 inhibitor: latest advances in medicinal chemistry

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