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CDK7 knockdown exhibited cell growth inhibition in cervical cancer cells. Notes: (A) qRT-PCR was performed to assess the CDK7 mRNA level after the knockdown of CDK7 using the CRISPR-Cas9 system in cervical cancer cells. (B) Western blot was used to detect the CDK7 protein level after the knockdown of CDK7 using the CRISPR-Cas9 system in cervical cancer cells. (C) A CCK-8 assay revealed the effects of cell proliferation after the knockdown of CDK7 in cervical cancer cells (*P<0.05, Student’s t-test). Abbreviations: CCK-8, Cell Counting Kit-8; CDK7, cyclin-dependent kinase 7.
Source publication
Background
The disordered cell cycle and dysregulated expression of numerous oncogenes involved in tumor-relevant processes are highly related to the tumorigenesis of cervical cancer. Cyclin-dependent kinase 7 (CDK7) constitutes the indispensable catalytic subunit of CDK-activating kinase (CAK), which is required for both cell cycle transition and...
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Purpose:
The BTF3 is involved in oncogenesis, while the biological roles in HSCC remain unclear. The aim of this study was to explore the impact of BTF3 knockdown on biological phenotypes of human HSCC in vivo and in vitro.
Methods:
The expression of BTF3 was assessed in HSCC and normal tissues. In vitro experiments were performed to explore imp...
Citations
... S7C and S9D), kidney cancer (35) (fig. S7E), and other cancers (36)(37)(38)(39)(40)(41)(42)(43) (Fig. 5F and figs. S7, D and F; S8C; and S9, E and F). ...
Cancers are often defined by the dysregulation of specific transcriptional programs; however, the importance of global transcriptional changes is less understood. Hypertranscription is the genome-wide increase in RNA output. Hypertranscription's prevalence, underlying drivers, and prognostic significance are undefined in primary human cancer. This is due, in part, to limitations of expression profiling methods, which assume equal RNA output between samples. Here, we developed a computational method to directly measure hypertranscription in 7494 human tumors, spanning 31 cancer types. Hypertranscription is ubiquitous across cancer, especially in aggressive disease. It defines patient subgroups with worse survival, even within well-established subtypes. Our data suggest that loss of transcriptional suppression underpins the hypertranscriptional phenotype. Single-cell analysis reveals hypertranscriptional clones, which dominate transcript production regardless of their size. Last, patients with hypertranscribed mutations have improved response to immune checkpoint therapy. Our results provide fundamental insights into gene dysregulation across human cancers and may prove useful in identifying patients who would benefit from novel therapies.
... CRISPR-Cas9-mediated exchange of PIM1 resulted in cell cycle arrest and apoptosis in HPV-driven most cancers (62). In addition, the genetic depletion of CDK7 using the CRISPR−Cas9 system exhibited great cell growth inhibition in cervical cancer cell lines (43). Additionally, HPV16-transformed cells with CRISPR−Cas9-mediated loss of p53 were inclined to lose dependence on the continuous expression of HPV oncogenes for proliferation (63). ...
Human papillomaviruses (HPVs) have been recognized as the etiologic agents of various cancers and are called HPV-driven cancers. Concerning HPV-mediated carcinogenic action, gene therapy can cure cancer at the molecular level by means of the correction of specific genes or sites. CRISPR-Cas9, as a novel genetic editing technique, can correct errors in the genome and change the gene expression and function in cells efficiently, quickly, and with relative ease. Herein, we overviewed studies of CRISPR-mediated gene remedies for HPV-driven cancers and summarized the potential applications of CRISPR-Cas9 in gene therapy for cancer.
... Several CDK7 inhibitors have showed anticancer effects by inducing cell apoptosis in AML, B-cell acute lymphoblastic leukemia, and solid tumors (Abudureheman et al., 2021;Clark et al., 2017;Hu et al., 2019;T. Huang et al., 2019;Li et al., 2017;Zhang et al., 2019;Zhong et al., 2019). In addition, inhibition of CDK7 has been associated with decreased expression of c-MYC and MCL1 (Clark et al., 2017;Li et al., 2017). ...
Acute myeloid leukemia (AML) is an aggressive blood cancer with a high rate of relapse associated with adverse survival outcomes, especially in elderly patients. An aberrant expression of cyclin dependent kinase 7 (CDK7) is associated with poor outcomes and CDK7 inhibition has showed antitumor activities in various cancers. We investigated the efficacy of YPN-005, a CDK7 inhibitor in AML cell lines, xenograft mouse model, and primary AML cells. YPN-005 effectively inhibited the proliferation of AML cells by inducing apoptosis and reducing phosphorylation of RNA polymerase II. The c-MYC expression decreased with treatment of YPN-005, and the effect of YPN-005 was negatively correlated with c-MYC expression. YPN-005 also showed antileukemic activities in primary AML cells, especially those harboring FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) mutation and in in vivo mouse model. Phosphorylated FLT3/Signal transducer and activator of transcription 5 (STAT5) was decreased and FLT3/STAT5 was downregulated with YPN-005 treatment. Our data suggest that YPN-005 has a role in treating AML by suppressing c-MYC and FLT3.
... Many studies (Akcakanat, Sahin, Shaye, Velasco, & Meric-Bernstam, 2008;Kawauchi, Ogasawara, Yasuyama, Otsuka, & Yamada, 2009;Le Grand et al., 2014;Leger et al., 2006) have found that cell cycle arrest was a very important feature that inhibits cancer cells proliferation. Zhong et al (2019) reported that THZ1, the cyclin-dependent kinase 7 (CDK7) inhibitor, had the activity of anti-cervical cancer, and its mechanism of action was to block cell cycle at the G2/M phase. We completely agree with that, and the same conclusion were also confirmed in our research. ...
Objective
In this study, black tea and Citrus maxima (BT-CM), yellow tea and C. maxima (YT-CM), green tea and C. maxima (GT-CM) as subjects, the active ingredient content and antioxidant activity of three tea and C. maxima (T-CM) were analyzed. The effects of three T-CMs on apoptosis of liver cells in vitro and its mechanism were further explored.
Methods
National standard method and HPLC were used for active ingredient analysis. MTT, cell flow cytometry and Western blot were used to analyze the effects of three T-CMs on cell proliferation, apoptosis, and its underlying molecular mechanism.
Results
The content of tea polyphenols, free amino acids, ratio of polyphenols and amino acids, ester catechins, non-ester catechins and caffeine in YT-CM and GT-CM was significantly higher than that of BT-CM. The in vitro antioxidant capacity of YT-CM and GT-CM was also significantly stronger than that of BT-CM. Three T-CMs had the effects of inhibiting proliferation, arresting cell cycle and inducing apoptosis in HepG2 and Bel7402 cells, especially YT-CM and GT-CM. Western blot analysis showed three T-CMs activated PI3K/AKT/mTOR signaling pathway and regulated the expression levels of apoptosis-related proteins Bax, Bcl-2 and Caspase-3/9. YT-CM and GT-CM had better ability to change the signal pathway than BT-CM.
Conclusion
In short, T-CMs, which combined different degrees of fermentation tea with C. maxima, were rich in nutrients and biologically active substances. T-CMs, especially YT-CM and GT-CM, are healthy drinks that help to prevent and treat liver cancer.
... Contradictorily, there is evidence denying antineoplastic potency of RNAi-based CDK4/6 or CDK2 knockdown [5,18]. In contrast, CRISPR or RNAi treatment targeting other CDKs (CDK7, -8, -9 for CRISPR and CDK1, -10, -12 for RNAi) [19][20][21][22][23] has successfully diminished tumor proliferation. ...
Cyclin-dependent kinase 4/6 (CDK4/6) are key regulators of the cell cycle and are deemed as critical therapeutic targets of multiple cancers. Various approaches have been applied to silence CDK4/6 at different levels, i.e., CRISPR to knock out at the DNA level, siRNA to inhibit translation, and drugs that target the protein of interest. Here we summarize the current status in this field, highlighting the mechanisms of small molecular inhibitors treatment and drug resistance. We describe approaches to combat drug resistance, including combination therapy and PROTACs drugs that degrade the kinases. Finally, critical issues and perspectives in the field are outlined.
... Knockdown or CRISPR/Cas9-mediated knockout of CDK7 results in reduced cell proliferation of gastric cancer and triple-negative breast cancer cells, respectively, highlighting a functional role of CDK7 in tumor cell growth [21,22]. In addition, THZ1, a covalent inhibitor of CDK7, reduces viability of a broad range of cancer cell lines from different entities, including thyroid carcinoma, lung squamous cell carcinoma, cervical cancer, colorectal cancer and pancreatic cancer, with T-cell acute lymphoblastic leukemia cells being especially sensitive [23][24][25][26][27]. THZ1 has also been shown to be effective in MYCN-driven neuroblastoma and small cell lung cancer cells, where treatment showed preferential inhibition of superenhancer-driven genes including MYCN and other oncogenes, suggesting that CDK7 inhibition might be an interesting therapeutic strategy for transcription-addicted and MYC-driven cancers [28,29]. ...
Inhibition of the dual function cell cycle and transcription kinase CDK7 is known to affect the viability of cancer cells, but the mechanisms underlying cell line-specific growth control remain poorly understood. Here, we employed a previously developed, highly specific small molecule inhibitor that non-covalently blocks ATP binding to CDK7 (LDC4297) to study the mechanisms underlying cell line-specific growth using a panel of genetically heterogeneous human pancreatic tumor lines as model system. Although LDC4297 diminished both transcription rates and CDK T-loop phosphorylation in a comparable manner, some PDAC lines displayed significantly higher sensitivity than others. We focused our analyses on two well-responsive lines (Mia-Paca2 and Panc89) that, however, showed significant differences in their viability upon extended exposure to limiting LDC4297 concentrations. Biochemical and RNAseq analysis revealed striking differences in gene expression and cell cycle control. Especially the downregulation of a group of cell cycle control genes, among them CDK1/2 and CDC25A/C, correlated well to the observed viability differences in Panc89 versus Mia-Paca2 cells. A parallel downregulation of regulatory pathways supported the hypothesis of a feedforward programmatic effect of CDK7 inhibitors, eventually causing hypersensitivity of PDAC lines.
... CDK7, which has multiple roles throughout the cell cycle, is involved in G2/M cell cycle progression. Here, it is needed to phosphorylate CDK1 and increase the expression of cyclin B1 [76]. These components are necessary for G2/M progression. ...
Estrogen receptor-positive (ER+) breast cancer is the most common form of breast cancer. Antiestrogens were the first therapy aimed at treating this subtype, but resistance to these warranted the development of a new treatment option. CDK4/6 inhibitors address this problem by halting cell cycle progression in ER+ cells, and have proven to be successful in the clinic. Unfortunately, both intrinsic and acquired resistance to CDK4/6 inhibitors are common. Numerous mechanisms of how resistance occurs have been identified to date, including the activation of prominent growth signaling pathways, the loss of tumor-suppressive genes, and noncanonical cell cycle function. Many of these have been successfully targeted and demonstrate the ability to overcome resistance to CDK4/6 inhibitors in preclinical and clinical trials. Future studies should focus on the development of biomarkers so that patients likely to be resistant to CDK4/6 inhibition can initially be given alternative methods of treatment.
... In addition to CDK4/6 inhibitors, several studies have shown a marked sensitivity of many cancer types to selective CDK7 inhibition [157][158][159][160][161][162][163][164][165] CDK7 is the main CDK activating kinases (CAK) phosphorylating CDK1, 2, 4 and 6, the main cell cycle-dependent CDKs 166 . Importantly, cancer cells are sensitive to CDK7 inhibitors at doses at which normal cells are insensitive, suggesting that treatments might be well tolerated in a clinical setting. ...
Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated by multiple evolutionarily conserved cell cycle control mechanisms, to ensure the production of two genetically identical cells. Cell cycle checkpoints operate as DNA surveillance mechanisms that prevent the accumulation and propagation of genetic errors during cell division. Checkpoints can delay cell cycle progression or, in response to irreparable DNA damage, induce cell cycle exit or cell death. Cancer-associated mutations that perturb cell cycle control allow continuous cell division chiefly by compromising the ability of cells to exit the cell cycle. Continuous rounds of division, however, create increased reliance on other cell cycle control mechanisms to prevent catastrophic levels of damage and maintain cell viability. New detailed insights into cell cycle control mechanisms and their role in cancer reveal how these dependencies can be best exploited in cancer treatment.
... It has been previously demonstrated that the inhibition of CDK7 function may provide an effective therapeutic method for the treatment of cervical cancer by suppressing cell cycle progression and transcriptional activity. THZ1 is a dominant inhibitor of CDK7 and can inhibit the cell cycle and repress essential oncogene transcription during tumorigenesis (52). THZ1-induced CDK7 inhibition downregulated cyclin B1, a cell cycle checkpoint mediator, and CDK1 phosphorylation, inducing cell cycle arrest at the G2/M phase (52). ...
... THZ1 is a dominant inhibitor of CDK7 and can inhibit the cell cycle and repress essential oncogene transcription during tumorigenesis (52). THZ1-induced CDK7 inhibition downregulated cyclin B1, a cell cycle checkpoint mediator, and CDK1 phosphorylation, inducing cell cycle arrest at the G2/M phase (52). CDK9 is located on chromosome 9q34.1 and is a main factor in RNA polymerase II transcription regulation (53). ...
Background:
The aim of this study was to identify downstream target genes and pathways regulated by THZ1 in nasopharyngeal carcinoma (NPC).
Methods:
The gene expression profile of GSE95750 in two NPC cell lines, untreated group and treated with THZ1 group, was analyzed. Differentially expressed genes (DEGs) were compared using the R-software. Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) was analyzed using Database for Annotation, Visualization, and Integrated Discovery (DAVID). Cytoscape was used for protein-protein interaction (PPI) analysis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verified the gene expression.
Results:
We identified 25 genes with increased expression and 567 genes with decreased expression in THZ1-treated NPC cells. The top 10 significantly DEGs between untreated group and THZ1 treated group were identified by qRT-PCR and the results were in agreement with RNA-seq. The total 592 DEGs were found enriched in 1,148 GO terms and 38 KEGG pathways. The most important enriched pathways identified were cell cycle related, and several related node genes were identified, such as CDC6, CDC34, CDK7, CDK9, CCNA2, CCNB1, CDT1, KIF11, LIN9, PLK1, and POLR family, which consistent with RNA-seq.
Conclusions:
Our results emphasize the differential genes and pathways occurring in THZ1-treated NPC cells, which increases our understanding of the anti-tumor mechanisms of THZ1.
... A number of covalent CDK7 inhibitors have also been developed, the first being THZ1 (Fig. 3b, Table 3), which targets a cysteine residue (Cys312) on a C-terminal extension just outside the ATP-binding site of CDK7 [20,132] and has strong activity in many cancer types (Table 3) [20,21,71,75,[114][115][116][117][118][119][120][121][122][123][124]. However, THZ1 also covalently links to CDK12 and CDK13, at Cys1039 and Cys1017, respectively, inhibiting their activity [20,132]. ...
Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.
