Mevan Fahmi Sami Jacksi

The role of EZH2 in TKS4-deficient colorectal carcinoma cells

2024-08

Annual Meeting of the Hungarian Biochemical Society

Tyrosine Kinase Substrate 4 (TKS4) is a large scaffold protein in the EGFR signal transduction pathway that is involved in several cellular processes, such as motility, reactive oxygen species-dependent processes, embryonic development and cancer. It is also implicated in a rare developmental disorder, Frank–ter Haar syndrome. Deletion of TKS4 resulted in increased migration, invasion, and EMT-like processes while a decrease in proliferation in HCT116 colorectal carcinoma cells. In this study we demonstrated that enhancer of zeste homolog 2 (EZH2), the histone methyltransferase of the PRC2 is involved in these changes in TKS4 deficient cells. An elevation of local and global H3K27me3 levels were detected in the TKS4 KO cells, and inhibition of EZH2 activity reversed the effects of TKS4 KO, reducing the EMT-like features, migration speed, and invasion capacity of the cells while the decrease in proliferation become stronger. The broader effects of deletion of TKS4 on the gene expression pattern of colorectal carcinoma cells were explored by transcriptome sequencing of WT and TKS4 KO cells before and after treatment with DZNep; the EZH2 inhibitor. Several protein coding genes with altered mRNA levels were identified in the TKS4 KO cell line, as well as a set of long non-coding RNAs, whose expression levels were restored after EZH2 inhibition. In summary, our findings demonstrate a significant perturbation of gene expression upon the deletion of TKS4, suggesting the involvement of different signal transduction pathways over the well-known EGFR signalling.

The role of EZH2 in TKS4-deficient colorectal carcinoma cells

2024-08

Annual Meeting of the Hungarian Biochemical Society

Tyrosine Kinase Substrate 4 (TKS4) is a large scaffold protein in the EGFR signal transduction pathway that is involved in several cellular processes, such as motility, reactive oxygen species-dependent processes, embryonic development and cancer. It is also implicated in a rare developmental disorder, Frank–ter Haar syndrome. Deletion of TKS4 resulted in increased migration, invasion, and EMT-like processes while a decrease in proliferation in HCT116 colorectal carcinoma cells. In this study we demonstrated that enhancer of zeste homolog 2 (EZH2), the histone methyltransferase of the PRC2 is involved in these changes in TKS4 deficient cells. An elevation of local and global H3K27me3 levels were detected in the TKS4 KO cells, and inhibition of EZH2 activity reversed the effects of TKS4 KO, reducing the EMT-like features, migration speed, and invasion capacity of the cells while the decrease in proliferation become stronger. The broader effects of deletion of TKS4 on the gene expression pattern of colorectal carcinoma cells were explored by transcriptome sequencing of WT and TKS4 KO cells before and after treatment with DZNep; the EZH2 inhibitor. Several protein coding genes with altered mRNA levels were identified in the TKS4 KO cell line, as well as a set of long non-coding RNAs, whose expression levels were restored after EZH2 inhibition. In summary, our findings demonstrate a significant perturbation of gene expression upon the deletion of TKS4, suggesting the involvement of different signal transduction pathways over the well-known EGFR signalling.

Morphological changes induced by TKS4 deficiency can be reversed by EZH2 inhibition

2024-03

HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Hungary

Progress Report