PMCID string | Title string | Sentences string |
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PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | In summary, combination treatment with THZ1 and imatinib significantly enhanced the GIST cell viability inhibition effect. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Fig. 5Combination treatment with THZ1 and imatinib for GIST. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | A CCK-8 viability assay following treatment for 72 h with escalating concentrations of THZ1 and imatinib in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | B GIST-T1 cells received single 20 nmol/L imatinib, THZ1 and a combination treatment for 72 h. GIST-882 cells received single 50 nmol/L imatinib, THZ1 and a combination treatment for 72 h. The cell viability of combination treatment group was significantly suppressed than monotherapy. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | C Synergy was calculated using CompuSyn, and a combination index value under 1.0 was considered to indicate synergy. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | D Immunoblotting analysis of cleaved caspase 3 and cleaved PARP protein expression after combination treatment with THZ1 and imatinib in GIST-T1 and GIST-882 cells for 24 h Combination treatment with THZ1 and imatinib for GIST. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | A CCK-8 viability assay following treatment for 72 h with escalating concentrations of THZ1 and imatinib in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | B GIST-T1 cells received single 20 nmol/L imatinib, THZ1 and a combination treatment for 72 h. GIST-882 cells received single 50 nmol/L imatinib, THZ1 and a combination treatment for 72 h. The cell viability of combination treatment group was significantly suppressed than monotherapy. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | C Synergy was calculated using CompuSyn, and a combination index value under 1.0 was considered to indicate synergy. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | D Immunoblotting analysis of cleaved caspase 3 and cleaved PARP protein expression after combination treatment with THZ1 and imatinib in GIST-T1 and GIST-882 cells for 24 h We next probed the mechanisms underlying the antitumour effect of THZ1 in GISTs. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Considering the prominent role of CDK7 in regulating the cell cycle and RNAPII-mediated transcription, we next assessed THZ1-induced transcriptional alterations in the gene expression profiles of GIST cells by whole-transcriptome sequencing (RNA-sequencing, RNA-seq) analyses. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Treatment with 50 nmol/L THZ1 for 6 h resulted in a dramatic decrease in global messenger RNA levels (Fig. 6A). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | A gene set (GOBP_CELL_CYCLE.v7.5.1) was downloaded and analysed with our RNA-seq data. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Among 1749 genes, 620 genes were significantly downregulated after THZ1 treatment (P < 0.05, log2-fold change > 1), and 320 genes were significantly upregulated (Fig. 6B). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | We performed gene ontology (GO) analysis to explore the functional enrichment of most differentially expressed genes. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | We found that THZ1-sensitive genes were associated with pathways involved in the regulation of transcription regulation by RNAPII (Fig. 6C). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Because CDK7 can preferentially downregulate RNAPII CTD phosphorylation, we detected the related proteins by western blotting. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | THZ1 treatment reduced the phosphorylation of Ser2, Ser5 and Ser7 on the Pol II CTD in GIST-T1 and GIST-882 cell lines in a dose-dependent manner (Fig. 6D). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Although our results showed that CDK7 knockdown led to cell cycle arrest in GIST cells, we found that CDK7 preferentially regulated transcription instead of directly regulating the cell cycle in GIST.Fig. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | 6CDK7 inhibition leads to the suppression of RNA transcription in GIST cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | A Heatmap showing the change in global active transcripts in GIST-T1 cells following treatment with 50 nmol THZ1 and DMSO for 6 h. B Heatmap showing the transcriptional changes in cell cycle-related genes from the gene set (GOBP_CELL_CYCLE.v7.5.1) in GIST-T1 cells after THZ1 treatment. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | C The enriched GO functional terms of the transcripts that were reduced over twofold in GIST-T1 cells following treatment with 50 nmol/L THZ1 for 6 h. D Immunoblot analyses of RNAPII, RNAPII CTD phosphorylation (S2, S5, and S7), and CDK7 in GIST-T1 and GIST-882 cells treated either with THZ1 or DMSO at the indicated concentrations for 24 h CDK7 inhibition leads to the suppression of RNA transcription in GIST cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | A Heatmap showing the change in global active transcripts in GIST-T1 cells following treatment with 50 nmol THZ1 and DMSO for 6 h. B Heatmap showing the transcriptional changes in cell cycle-related genes from the gene set (GOBP_CELL_CYCLE.v7.5.1) in GIST-T1 cells after THZ1 treatment. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | C The enriched GO functional terms of the transcripts that were reduced over twofold in GIST-T1 cells following treatment with 50 nmol/L THZ1 for 6 h. D Immunoblot analyses of RNAPII, RNAPII CTD phosphorylation (S2, S5, and S7), and CDK7 in GIST-T1 and GIST-882 cells treated either with THZ1 or DMSO at the indicated concentrations for 24 h Previous research revealed that THZ1 treatment induces EGFR and PDGFRa expression and multiple downstream oncogenic signalling pathways in glioma . |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | CDK7 inhibition suppresses GIST cell proliferation and survival via inhibition of transcription. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Therefore, we analysed the c-KIT expression changes after CDK7 knockdown or THZ1 treatment. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Interestingly, we observed that c-KIT mRNA and protein levels were significantly decreased after CDK7 knockdown (Fig. 7A, B) and THZ1 treatment (Fig. 7C–E). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The phosphorylated forms of AKT and ERK were all prominently downregulated by CDK7 or THZ1 knockdown (Fig. 7B, E). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Compared with monotherapy with imatinib or THZ1, the combination of the two more effectively inactivated the c-KIT and downstream AKT and ERK signalling cascades (Fig. 7F).Fig. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | 7CDK7 inhibition leads to the suppression of c-KIT transcriptional activity and protein expression in GIST cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | A, B qRT–PCR and immunoblotting analysis of c-KIT expression after siRNA-mediated CDK7 knockdown in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | C, D qRT–PCR and immunofluorescence assays showed that c-KIT expression changed after THZ1 treatment in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | E Immunoblotting analysis showed that the expression of c-KIT and downstream ERK and AKT signalling pathway components was inhibited following THZ1 treatment at the indicated concentration in GIST-T1 and GIST-882 cells for 24 h. F Immunoblotting analysis indicated that combination treatment with imatinib and THZ1 enhanced c-KIT expression inhibition in GIST-T1 and GIST-882 cells for 24 h CDK7 inhibition leads to the suppression of c-KIT transcriptional activity and protein expression in GIST cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | A, B qRT–PCR and immunoblotting analysis of c-KIT expression after siRNA-mediated CDK7 knockdown in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | C, D qRT–PCR and immunofluorescence assays showed that c-KIT expression changed after THZ1 treatment in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | E Immunoblotting analysis showed that the expression of c-KIT and downstream ERK and AKT signalling pathway components was inhibited following THZ1 treatment at the indicated concentration in GIST-T1 and GIST-882 cells for 24 h. F Immunoblotting analysis indicated that combination treatment with imatinib and THZ1 enhanced c-KIT expression inhibition in GIST-T1 and GIST-882 cells for 24 h Previous studies have indicated that THZ1 impairs the transcriptional activity of the superenhancers (SEs) of oncogenic genes, so to explore the mechanism underlying c-KIT transcription inhibition induced by CDK7 knockdown, we investigated SEs. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Previous research has identified a cluster of SEs of GISTs, including MEIS1, OSR1, and FOXF1. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Interestingly, we found that odd-skipped related transcription factor 1 (OSR1) was the most significantly downregulated gene in GIST-T1 cells after THZ1 treatment (Fig. 8A, Additional file 2: Table S1). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Immunoblotting analyses verified that OSR1 expression was significantly inhibited by THZ1 treatment with CDK7 knockdown (Fig. 8B, C). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Next, we searched the gene expression profile in the Oncomine database and MediSapiens IST Online transcriptome database. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | As shown in Fig. 8D, E, OSR1 was significantly upregulated in GIST compared with normal gastric tissue and was highly expressed in GIST and prostate cancer compared with other human cancers. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | To verify this result, we detected OSR1 expression in clinical samples of GIST, gastrointestinal leiomyoma and schwannoma. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | As expected, OSR1 was significantly highly expressed in GIST (Fig. 8F). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Furthermore, we performed correlation analysis of OSR1 and c-KIT expression, and the results showed that OSR1 levels were positively associated with c-KIT levels (r = 0.407, P < 0.001, Fig. 8G). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The qRT–PCR and immunoblotting analyses showed that OSR1 knockdown significantly inhibited c-KIT transcript and protein expression in GIST-T1 and GIST-882 cells (Fig. 8H, I). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | In contrast, overexpressed OSR1 increased c-KIT expression (Fig. 8J). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | When CDK7 siRNA and OSR1 plasmid were cotransfected into GIST-T1 and GIST-882 cells, the inhibition of c-KIT expression was reversed (Fig. 8K). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Collectively, these results revealed that CDK7 mediates c-KIT expression through OSR1.Fig. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | 8CDK7 inhibits c-KIT expression through OSR1 in GIST. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | A Volcano plot of RNA-seq data displaying the distribution of differential gene expression between THZ1 treatment and DMSO treatment. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The upregulated and downregulated genes are highlighted in red and blue, respectively. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The results illustrated that OSR1 was the top downregulated gene with the lowest P value. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | B, C qRT–PCR and immunoblotting analyses showed that OSR1 expression was inhibited by CDK7 knockdown or THZ1 treatment in a dose-dependent manner. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | OSR1 expression was inhibited by CDK7 knockdown in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | D Gene expression profile in the Oncomine database. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The results showed that OSR1 was significantly upregulated in GIST compared with normal gastric tissue. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | E Gene expression profile in the MediSapiens IST Online transcriptome database. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The results showed that OSR1 was uniquely overexpressed in GIST and prostate cancer compared with other cancer types. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | F Immunoblot analyses of OSR1 expression in clinical sample tissues of GIST, gastrointestinal leiomyoma and schwannoma. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The expression of OSR1 was significantly higher in GIST than in leiomyoma and schwannoma. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | G Data from the MediSapiens database showed that c-KIT and OSR1 expression levels were positively correlated (n = 77, r = 0.407, P < 0.001). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | H, I qRT–PCR and immunoblotting analyses showed that OSR1 knockdown significantly inhibited c-KIT mRNA and protein expression in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | J Immunoblot analyses showed that OSR1 overexpression promoted c-KIT expression in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | K The inhibitory effect of c-KIT expression was reversed when CDK7 siRNA and OSR1 plasmid were cotransfected into GIST-T1 and GIST-882 cells CDK7 inhibits c-KIT expression through OSR1 in GIST. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | A Volcano plot of RNA-seq data displaying the distribution of differential gene expression between THZ1 treatment and DMSO treatment. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The upregulated and downregulated genes are highlighted in red and blue, respectively. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The results illustrated that OSR1 was the top downregulated gene with the lowest P value. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | B, C qRT–PCR and immunoblotting analyses showed that OSR1 expression was inhibited by CDK7 knockdown or THZ1 treatment in a dose-dependent manner. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | OSR1 expression was inhibited by CDK7 knockdown in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | D Gene expression profile in the Oncomine database. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The results showed that OSR1 was significantly upregulated in GIST compared with normal gastric tissue. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | E Gene expression profile in the MediSapiens IST Online transcriptome database. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The results showed that OSR1 was uniquely overexpressed in GIST and prostate cancer compared with other cancer types. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | F Immunoblot analyses of OSR1 expression in clinical sample tissues of GIST, gastrointestinal leiomyoma and schwannoma. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The expression of OSR1 was significantly higher in GIST than in leiomyoma and schwannoma. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | G Data from the MediSapiens database showed that c-KIT and OSR1 expression levels were positively correlated (n = 77, r = 0.407, P < 0.001). |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | H, I qRT–PCR and immunoblotting analyses showed that OSR1 knockdown significantly inhibited c-KIT mRNA and protein expression in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | J Immunoblot analyses showed that OSR1 overexpression promoted c-KIT expression in GIST-T1 and GIST-882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | K The inhibitory effect of c-KIT expression was reversed when CDK7 siRNA and OSR1 plasmid were cotransfected into GIST-T1 and GIST-882 cells Despite advances in genetic alteration diagnoses and tyrosine kinase inhibitor treatment, the prognosis of patients with GIST remains unsatisfactory, especially for high-risk GISTs. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The effectiveness of standard targeted therapy is hampered by secondary resistance following initial responses due to acquired secondary mutations . |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | CDKs play a significant role in regulating the cell cycle and gene transcription. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | CDK7 is one of the subunits of the multiprotein transcription factor complex TFIIH, and it is critical for facilitating transcription initiation and elongation via phosphorylation of the CTD of RNAPII . |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | CDK7 has been reported to be a potential therapeutic target in transcription-dependent cancers and is associated with a poor prognosis [21, 24–28]. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | However, the role of CDK7 in GIST tumorigenesis remains unknown. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | In our study, we conducted an analysis of the transcriptomic data of 65 GIST patients from the GEO public database. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | The CDK4, CDK7 and CDK9 mRNA levels were significantly higher than those of other CDKs, and further, we found that the CDK7 mRNA level was significantly elevated in high-risk GISTs, while there was no significant difference in CDK4 and CDK9. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Previously, Yu Liu analysed quantitative proteome profiling of GIST and adjacent normal tissue and found that several kinases were significantly upregulated in GIST, including KIT and CDK7 . |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Consistent with this, we validated with tissue microarrays (TMAs) that CDK7 overexpression in GISTs was correlated with tumour progression and an unfavourable prognosis. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Inhibition of CDK7 or CDK7 inhibitor treatment significantly inhibited GIST cell proliferation. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | These results revealed that CDK7 might play an oncogenic role in GIST progression. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | GISTs exhibit a homogeneous repertoire of transcription factors, which supports its associated gene expression program throughout all stages of the disease. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Several core transcription factors have been revealed to play essential roles in driving GIST cell proliferation and metastasis by binding to enhancers of GIST-associated genes and facilitating KIT gene expression [13–15]. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Moreover, a previous study revealed that the KIT-regulated enhancer domain in GISTs could be targeted by BRD4, a key activator of RNAPII transcription at active chromatin marks, and the BET bromodomain inhibitor (BBI) can downregulate KIT transcription . |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Therefore, characterization of transcription factor deregulation in GIST may provide innovative insights into the pathogenesis mechanisms and offer new therapeutic approaches. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | In our study, RNA-seq analysis was used to detect alterations in total transcripts in GIST cells after treatment with THZ1. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | We observed that a cluster of genes was particularly sensitive to THZ1 treatment and was mainly enriched in biological processes of transcription regulation mediated by RNAPII. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Considering the original genetic alteration of GIST, we investigated the transcriptional activity and protein expression of c-KIT after CDK7 knockdown or THZ1 treatment. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | Interestingly, we found that c-KIT transcription and protein expression were significantly inhibited after CDK7 knockdown or THZ1 treatment in both GIST T1 and 882 cells. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | This result indicated that CDK7 might be a key driver of c-KIT expression in GIST and that it is a possible therapeutic target. |
PMC9454178 | THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours | CDK inhibitors are of great interest as novel therapeutic agents against cancer, and several CDK inhibitors have been applied in the clinic. |
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