Gene Summary

Gene:CDK7; cyclin dependent kinase 7
Aliases: CAK, CAK1, HCAK, MO15, STK1, CDKN7, p39MO15
Summary:The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression. This protein forms a trimeric complex with cyclin H and MAT1, which functions as a Cdk-activating kinase (CAK). It is an essential component of the transcription factor TFIIH, that is involved in transcription initiation and DNA repair. This protein is thought to serve as a direct link between the regulation of transcription and the cell cycle. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase 7
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (44)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Breast Cancer
  • Synthetic Lethal Mutations
  • Transcription Factors
  • Pyrimidines
  • Cell Proliferation
  • Proportional Hazards Models
  • Lung Cancer
  • Triple Negative Breast Cancer
  • DNA-Binding Proteins
  • Cell Survival
  • Xenograft Models
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • Xeroderma Pigmentosum
  • Genotype
  • Gene Expression Profiling
  • Down-Regulation
  • Cell Cycle
  • Antineoplastic Agents
  • Genetic Predisposition
  • Squamous Cell Carcinoma
  • Cyclin-Dependent Kinases
  • Phosphorylation
  • Transcription Factor TFIIH
  • Mice, Inbred NOD
  • Protein Kinase Inhibitors
  • Apoptosis
  • Western Blotting
  • Nuclear Proteins
  • DNA Repair
  • Phenylenediamines
  • Up-Regulation
  • RB1
  • BCL2 protein
  • Estrogen Receptor alpha
  • Mutation
  • Drug Resistance
  • Single Nucleotide Polymorphism
  • Chromosome 5
  • Neuroblastoma
  • Dose-Response Relationship, Drug
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CDK7 (cancer-related)

Sharifnia T, Wawer MJ, Chen T, et al.
Small-molecule targeting of brachyury transcription factor addiction in chordoma.
Nat Med. 2019; 25(2):292-300 [PubMed] Free Access to Full Article Related Publications
Chordoma is a primary bone cancer with no approved therapy

Fisher RP
Cdk7: a kinase at the core of transcription and in the crosshairs of cancer drug discovery.
Transcription. 2019; 10(2):47-56 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
The transcription cycle of RNA polymerase II (Pol II) is regulated by a set of cyclin-dependent kinases (CDKs). Cdk7, associated with the transcription initiation factor TFIIH, is both an effector CDK that phosphorylates Pol II and other targets within the transcriptional machinery, and a CDK-activating kinase (CAK) for at least one other essential CDK involved in transcription. Recent studies have illuminated Cdk7 functions that are executed throughout the Pol II transcription cycle, from promoter clearance and promoter-proximal pausing, to co-transcriptional chromatin modification in gene bodies, to mRNA 3´-end formation and termination. Cdk7 has also emerged as a target of small-molecule inhibitors that show promise in the treatment of cancer and inflammation. The challenges now are to identify the relevant targets of Cdk7 at each step of the transcription cycle, and to understand how heightened dependence on an essential CDK emerges in cancer, and might be exploited therapeutically.

Decaesteker B, Denecker G, Van Neste C, et al.
TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets.
Nat Commun. 2018; 9(1):4866 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.

Minzel W, Venkatachalam A, Fink A, et al.
Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models.
Cell. 2018; 175(1):171-185.e25 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2

Durbin AD, Zimmerman MW, Dharia NV, et al.
Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry.
Nat Genet. 2018; 50(9):1240-1246 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Childhood high-risk neuroblastomas with MYCN gene amplification are difficult to treat effectively

Wong RWJ, Ishida T, Sanda T
Targeting General Transcriptional Machinery as a Therapeutic Strategy for Adult T-Cell Leukemia.
Molecules. 2018; 23(5) [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Cancer cells are highly reliant on certain molecular pathways, which support their survival and proliferation. The fundamental concept of molecularly targeted therapy is to target a protein that is specifically deregulated or overexpressed in cancer cells. However, drug resistance and tumor heterogeneity are major obstacles in the development of specific inhibitors. Additionally, many driver oncogenes exert their oncogenic property via abnormal expression without having genetic mutations. Interestingly, recent accumulating evidence has demonstrated that many critical cancer genes are driven by a unique class of enhancers termed super-enhancers. Genes associated with super-enhancers are relatively more susceptible to the inhibition of general transcriptional machinery compared with genes that are regulated by typical enhancers. Cancer cells are more sensitive to treatment with small-molecule inhibitors of CDK7 or BRD4 than non-transformed cells. These findings proposed a novel strategy to identify functionally important genes as well as novel therapeutic modalities in cancer. This approach would be particularly useful for genetically complicated cancers, such as adult T-cell leukemia (ATL), whereby a large mutational burden is present, but the functional consequences of each mutation have not been well-studied. In this review, we discuss recent findings on super-enhancers, underlying mechanisms, and the efficacy of small-molecule transcriptional inhibitors in ATL.

Zahra A, Rubab I, Malik S, et al.
Meta-Analysis of miRNAs and Their Involvement as Biomarkers in Oral Cancers.
Biomed Res Int. 2018; 2018:8439820 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Oral Squamous Cell Carcinoma (OSCC) is one of the most common cancers worldwide. Recent studies have highlighted the role of miRNA in disease pathology, indicating its potential use as an early diagnostic marker. Dysregulated expression of miRNAs is known to affect cell growth, and these may function as tumor suppressors or oncogenes in various cancers. The main objective of this study was to characterize the extracellular miRNAs involved in

Jeselsohn R, Bergholz JS, Pun M, et al.
Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations.
Cancer Cell. 2018; 33(2):173-186.e5 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER

Eliades P, Abraham BJ, Ji Z, et al.
High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma.
J Invest Dermatol. 2018; 138(7):1582-1590 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Cutaneous melanoma is an aggressive tumor that accounts for most skin cancer deaths. Among the physiological barriers against therapeutic success is a strong survival program driven by genes such as MITF that specify melanocyte identity, a phenomenon known in melanoma biology as lineage dependency. MITF overexpression is occasionally explained by gene amplification, but here we show that super-enhancers are also important determinants of MITF overexpression in some melanoma cell lines and tumors. Although compounds that directly inhibit MITF are unavailable, a covalent CDK7 inhibitor, THZ1, has recently been shown to potently suppress the growth of various cancers through the depletion of master transcription-regulating oncogenes and the disruption of their attendant super-enhancers. We also show that melanoma cells are highly sensitive to CDK7 inhibition both in vitro and in vivo and that THZ1 can dismantle the super-enhancer apparatus at MITF and SOX10 in some cell lines, thereby extinguishing their intracellular levels. Our results show a dimension to MITF regulation in melanoma cells and point to CDK7 inhibition as a potential strategy to deprive oncogenic transcription and suppress tumor growth in melanoma.

Iniguez AB, Stolte B, Wang EJ, et al.
EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma.
Cancer Cell. 2018; 33(2):202-216.e6 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI-dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression. The combination of these molecules with PARP inhibitors showed striking synergy in cell viability and DNA damage assays in vitro and in multiple models of Ewing sarcoma, including a PDX, in vivo without hematopoietic toxicity.

Xia Y, Liu X, Zou C, et al.
Garcinone C exerts antitumor activity by modulating the expression of ATR/Stat3/4E‑BP1 in nasopharyngeal carcinoma cells.
Oncol Rep. 2018; 39(3):1485-1493 [PubMed] Related Publications
Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and is typically treated with radiotherapy and chemotherapy. Garcinone C, a natural compound isolated from Garcinia oblongifolia Champ., is a xanthone derivative with potential cytotoxic effects on certain cancers. However, there are limited studies regarding its effects on NPC cells, and its mechanism of action in NPC remains unknown. In the present study, we found that garcinone C significantly inhibited cell viability of the human NPC cell lines CNE1, CNE2, HK1 and HONE1. This inhibition was exerted in a time‑ and dose‑dependent manner. Flow cytometry demonstrated that garcinone C arrested the cell cycle at the S phase. Moreover, with 10 µM of high‑dose garcinone C treatment, the cells exhibited necrotic morphology changes including cell swelling, rough endoplasmic reticulum degranulation, endoplasmic reticulum dilatation, mitochondrial swelling and vacuolar degeneration. In addition, we found that garcinone C stimulated the expression levels of ATR and 4E‑BP1, while efficiently inhibiting the expression levels of cyclin B1, cyclin D1, cyclin E2, cdc2, CDK7 and Stat3. Collectively, the ability of garcinone C to inhibit NPC in growth in vitro suggested that garcinone C may be a novel agent for the management of NPC.

Terai H, Kitajima S, Potter DS, et al.
ER Stress Signaling Promotes the Survival of Cancer "Persister Cells" Tolerant to EGFR Tyrosine Kinase Inhibitors.
Cancer Res. 2018; 78(4):1044-1057 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells that survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib + THZ1 (CDK7/12 inhibitor) combination therapy, a combination previously shown to suppress drug-tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP, and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response associated with STING upregulation, promoting protumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.

Rusan M, Li K, Li Y, et al.
Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression.
Cancer Discov. 2018; 8(1):59-73 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and

Wong RWJ, Ngoc PCT, Leong WZ, et al.
Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia.
Blood. 2017; 130(21):2326-2338 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
A number of studies have recently demonstrated that super-enhancers, which are large cluster of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 and mediator bindings, are frequently associated with genes that control and define cell identity during normal development. Super-enhancers are also often enriched at cancer genes in various malignancies. The identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. In this study, we performed enhancer profiling using primary leukemia samples from adult T-cell leukemia/lymphoma (ATL), which is a genetically heterogeneous intractable cancer. Super-enhancers were enriched at genes involved in the T-cell activation pathway, including

Yuan J, Jiang YY, Mayakonda A, et al.
Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma.
Cancer Res. 2017; 77(23):6614-6626 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to inhibitors of cyclin-dependent kinases (CDK), especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced antineoplastic activities both

Berico P, Coin F
Is TFIIH the new Achilles heel of cancer cells?
Transcription. 2018; 9(1):47-51 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
TFIIH is a 10-subunit complex involved in transcription and DNA repair. It contains several enzymatic activities including a ATP-dependent DNA translocase in XPB and a cyclin-dependent kinase in CDK7. Recently the discovery of several XPB and CDK7 inhibitors with specific impact on the transcriptional addiction of many tumors pinpointed these activities as potential target in cancer chemotherapy. Unexpectedly a basal transcription factor involved in global mRNA expression now emerges a one of the most clinically promising Achilles heels of cancerous cells. These inhibitors also proved to be useful tools to unveil new functions of TFIIH in gene expression.

Han Y, Huang W, Liu J, et al.
Triptolide Inhibits the AR Signaling Pathway to Suppress the Proliferation of Enzalutamide Resistant Prostate Cancer Cells.
Theranostics. 2017; 7(7):1914-1927 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Enzalutamide is a second-generation androgen receptor (AR) antagonist for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Unfortunately, AR dysfunction means that resistance to enzalutamide will eventually develop. Thus, novel agents are urgently needed to treat this devastating disease. Triptolide (TPL), a key active compound extracted from the Chinese herb Thunder God Vine (

Cassidy RJ, Zhang X, Patel PR, et al.
Next-generation sequencing and clinical outcomes of patients with lung adenocarcinoma treated with stereotactic body radiotherapy.
Cancer. 2017; 123(19):3681-3690 [PubMed] Related Publications
BACKGROUND: Genetic aberrations are well characterized in lung adenocarcinomas (LACs) and clinical outcomes have been influenced by targeted therapies in the advanced setting. Stereotactic body radiotherapy (SBRT) is the standard-of-care therapy for patients with nonoperable, early-stage LAC, but to the authors' knowledge, no information is available regarding the impact of genomic changes in these patients. The current study sought to determine the frequency and clinical impact of genetic aberrations in this population.
METHODS: Under an Institutional Review Board-approved protocol, the records of 242 consecutive patients with early-stage lung cancers were reviewed; inclusion criteria included LAC histology with an adequate tumor sample for the successful use of next-generation sequencing and fluorescence in situ hybridization testing. Univariate analysis was performed to identify factors associated with clinical outcomes.
RESULTS: LAC samples from 98 of the 242 patients were reviewed (40.5%), of whom 45 patients (46.0%) had genetic testing. The following mutations were noted: KRAS in 20.0% of samples, BRAF in 2.2% of samples, SMAD family member 4 (SMAD4) in 4.4% of samples, epidermal growth factor receptor (EGFR) in 15.6% of samples, STK1 in 2.2% of samples, tumor protein 53 (TP53) in 15.6% of samples, and phosphatase and tensin homolog (PTEN) in 2.2% of samples. The following gene rearrangements were observed: anaplastic lymphoma kinase (ALK) in 8.9% of samples, RET in 2.2% of samples, and MET amplification in 17.8% of samples. The median total delivered SBRT dose was 50 grays (range, 48-60 grays) over a median of 5 fractions (range, 3-8 fractions). The KRAS mutation was associated with worse local control (odds ratio [OR], 3.64; P<.05). MET amplification was associated with worse regional (OR, 4.64; P<.05) and distant (OR, 3.73; P<.05) disease control.
CONCLUSIONS: To the authors' knowledge, the current series is the first to quantify genetic mutations and their association with clinical outcomes in patients with early-stage LAC treated with SBRT. KRAS mutations were associated with worse local control and MET amplification was associated with worse regional and distant disease control, findings that need to be validated in a prospective setting. Cancer 2017;123:3681-3690. © 2017 American Cancer Society.

Zhang Z, Peng H, Wang X, et al.
Preclinical Efficacy and Molecular Mechanism of Targeting CDK7-Dependent Transcriptional Addiction in Ovarian Cancer.
Mol Cancer Ther. 2017; 16(9):1739-1750 [PubMed] Related Publications
Ovarian cancer remains a significant cause of gynecologic cancer mortality, and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential antitumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identified THZ1, a recently developed covalent CDK7 inhibitor, as a new transcription-targeting compound that exerted broad cytotoxicity against ovarian tumors. Mechanistically, CDK7 represented a previously unappreciated actionable vulnerability in ovarian cancer, and CDK7 inhibition led to a pronounced dysregulation of gene transcription, with a preferential repression of E2F-regulated genes and transcripts associated with super-enhancers. Our findings revealed the molecular underpinnings of THZ1 potency and established pharmaceutically targeting transcriptional addiction as a promising therapeutic strategy in aggressive ovarian cancer.

Nagaraja S, Vitanza NA, Woo PJ, et al.
Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma.
Cancer Cell. 2017; 31(5):635-652.e6 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.

Kavarthapu R, Dufau ML
Essential role of endogenous prolactin and CDK7 in estrogen-induced upregulation of the prolactin receptor in breast cancer cells.
Oncotarget. 2017; 8(16):27353-27363 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Our early studies have shown that Estradiol (E2)/Estrogen Receptor α (ER) in a non-DNA dependent manner through complex formation with C/EBPβ/SP1 induced transcriptional activation of the generic hPIII promoter and expression of the Prolactin Receptor (PRLR) receptor in MCF-7 cells. Subsequent studies demonstrated effects of unliganded ERα with requisite participation of endogenous PRL on the activation of PRLR transcription. Also, EGF/ERBB1 in the absence of PRL and E2 effectively induced upregulation of the PRLR. In this study we have delineated the transcriptional mechanism of upregulation of PRLR receptor induced by E2 incorporating knowledge of the various transcriptional upregulation modalities from our previous studies. Here, we demonstrate an essential requirement of STAT5a induced by PRL via PRLR receptor which associates at the promoter and its interaction with phoshoERα S118. Knock-down of PRL by siRNA significantly reduced E2-induced PRLR promoter activity, mRNA and protein expression, recruitment of ERα to the complex at promoter, C/EBPβ association to its DNA site and productive complex formation at hPIII promoter. The specific CDK7 inhibitor (THZ1) that attenuates E2-induced ERα phosphorylation at S118 abrogated E2-induced PRLR promoter activation. Further studies demonstrated that E2 induced cell migration was inhibited by PRL siRNA and THZ1 indicating its dependence on PRL/PRLR and CDK7, respectively. Our studies have demonstrated the essential role of endogenous PRL and CDK7 in the upregulation of PRLR by E2 and provide insights for therapeutic approaches that will mitigate the transcription/expression of PRLR and its participation in breast cancer progression fueled by E2 and PRL via their cognate receptors.

Li J, Zhang Z, Xiong L, et al.
SNHG1 lncRNA negatively regulates miR-199a-3p to enhance CDK7 expression and promote cell proliferation in prostate cancer.
Biochem Biophys Res Commun. 2017; 487(1):146-152 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) have been reported to play vital roles in the development of human cancers, but our understandings of most lncRNAs in cancers are still limited. Recently, accumlating evidences have showed that many RNA transcripts could function as competing endogenous RNAs (ceRNAs) by competitively binding common microRNAs. In this study, we demonstrated that a lncRNA, Small Nucleolar RNA Host Gene 1 (SNHG1), as a ceRNA for miR-199a-3p, played a critical role in prostate cancer cell proliferation. We found that SNHG1 was aberrantly up-regulated in prostate carcinoma tissues; while, miR-199a-3p was abnormally down-regulated. The level of SNHG1 in prostate cancer was significantly negatively correlated with that of miR-199a-3p. Our data indicated that SNHG1 could interact with miR-199a-3p and inhibit the activity of miR-199a-3p in prostate cancer cells. In addition, miR-199a-3p could target the 3' UTR of CDK7 and suppress CDK7 expression. More importantly, SNHG1 increased CDK7 expression by competitively binding miR-199a-3p, and then promoted cell proliferation and cell cycle progression in prostate cancer. Taken together, these findings elucidated a novel mechanism of prostate cancer progression. Thus, SNHG1 might serve as a potential target for prostate cancer therapies.

Cayrol F, Praditsuktavorn P, Fernando TM, et al.
THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors.
Nat Commun. 2017; 8:14290 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.

Paparidis NF, Durvale MC, Canduri F
The emerging picture of CDK9/P-TEFb: more than 20 years of advances since PITALRE.
Mol Biosyst. 2017; 13(2):246-276 [PubMed] Related Publications
CDK9 is a prominent member of the transcriptional CDKs subfamily, a group of kinases whose function is to control the primary steps of mRNA synthesis and processing by eukaryotic RNA polymerase II. As a cyclin-dependent kinase, CDK9 activation in vivo depends upon its association with T-type cyclins to assemble the positive transcription elongation factor (P-TEFb). Although CDK9/P-TEFb phosphorylates the C-terminal domain of RNAP II in the same positions targeted by CDK7 (TFIIH) and CDK8 (Mediator), the former does not participate in the transcription initiation, but rather plays a unique role by driving the polymerase to productive elongation. In addition to RNAP II CTD, the negative transcription elongation factors DSIF and NELF also represent major CDK9 substrates, whose phosphorylation is required to overcome the proximal pause of the polymerase. CDK9 is recruited to specific genes through proteins that interact with both P-TEFb and distinct elements in DNA, RNA or chromatin, where it modulates the activity of individual RNAP II transcription complexes. The regulation of CDK9 function is an intricate network that includes post-translational modifications (phosphorylation/dephosphorylation and acetylation/deacetylation of key residues) as well as the association of P-TEFb with various proteins that can stimulate or inhibit its kinase activity. Several cases of CDK9 deregulation have been linked to important human diseases, including various types of cancer and also AIDS (due to its essential role in HIV replication). Not only HIV, but also many other human viruses have been shown to depend strongly on CDK9 activity to be transcribed within host cells. This review summarizes the main advances made on CDK9/P-TEFb field in more than 20 years, introducing the structural, functional and genetic aspects that have been elucidated ever since.

Patel H, Abduljabbar R, Lai CF, et al.
Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer.
Clin Cancer Res. 2016; 22(23):5929-5938 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
PURPOSE: CDK-activating kinase (CAK) is required for the regulation of the cell cycle and is a trimeric complex consisting of cyclin-dependent kinase 7 (CDK7), Cyclin H, and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-α (ER). Deregulation of cell cycle and transcriptional control are general features of tumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics.
EXPERIMENTAL DESIGN: mRNA and protein expression of CDK7 and its essential cofactors cyclin H and MAT1 were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of >900 breast cancers was used to determine the association with clinicopathologic features and patient outcome.
RESULTS: We show that expressions of CDK7, cyclin H, and MAT1 are all closely linked at the mRNA and protein level, and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumor grade and size, and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ER expression and in particular with phosphorylation of ER at serine 118, a site important for ER transcriptional activity.
CONCLUSIONS: Expressions of components of the CAK complex, CDK7, MAT1, and Cyclin H are elevated in breast cancer and correlate with ER. Like ER, CDK7 expression is inversely proportional to poor prognostic factors and survival. Clin Cancer Res; 22(23); 5929-38. ©2016 AACR.

Harrod A, Fulton J, Nguyen VTM, et al.
Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer.
Oncogene. 2017; 36(16):2286-2296 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations. Understanding how these mutations impact on ER function is a prerequisite for identifying methods to treat breast cancer patients featuring such mutations. Towards this end, we used CRISPR-Cas9 genome editing to make a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line. Genomic analyses using RNA-seq and ER ChIP-seq demonstrated that the Y537S mutation promotes constitutive ER activity globally, resulting in estrogen-independent growth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen and fulvestrant. Further, we show that the basal transcription factor TFIIH is constitutively recruited by ER-Y537S, resulting in ligand-independent phosphorylation of Serine 118 (Ser118) by the TFIIH kinase, cyclin-dependent kinase (CDK)7. The CDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growth of MCF7-Y537S cells. These studies confirm the functional importance of ER mutations in endocrine resistance, demonstrate the utility of knock-in mutational models for investigating alternative therapeutic approaches and highlight CDK7 inhibition as a potential therapy for endocrine-resistant breast cancer mediated by ER mutations.

Naseh G, Mohammadifard M, Mohammadifard M
Upregulation of cyclin-dependent kinase 7 and matrix metalloproteinase-14 expression contribute to metastatic properties of gastric cancer.
IUBMB Life. 2016; 68(10):799-805 [PubMed] Related Publications
The aim of this study was to evaluate the protein and mRNA expressions of matrix metalloproteinase-14 (MMP14) and CDK7 in gastric cancer (GC) tissues. Upregulation of MMP14 mRNA level was observed in GC tissues when compared with the matched normal tissues (mean ± SD: 3.92 ± 1.15 vs. 1.35 ± 0.81, P < 0.001). This study indicated that mRNA levels of CDK7 were statistically overexpressed in GC when compared with matched normal tissues (4.12 ± 0.84 vs. 1.43 ± 0.71, P < 0.001). The protein levels of MMP14 were found to be increased in GC (60.41%; P < 0.001). The expression of CDK7 was higher in GC tissues than matched normal tissues (70.83; P < 0.001). We found that high MMP14 expression was related to advanced TNM stage (P = 0.004), tumor grade (P = 0.002), and lymph node metastasis (P = 0.015), but no association with other clinical variables (P > 0.05). In addition, high expression of CDK7 was significantly linked to advanced TNM stage (P = 0.001), pathological grade (P = 0.012), and presence of lymph node metastasis (P = 0.009), while no correlation between CDK7 expression and other clinical variables, such as age and gender, distance metastasis. The patients with high expression of MMP14 and CDK7 exhibited worse survival time than those with higher levels. Cox multivariate regression analysis clearly showed that high expression of MMP14 and CDK7 was independent prognostic factors for overall survival in patients with GC. Taken together, these results indicated the overexpression of above markers in the progression and the tumorigenesis of GC and overall patient survival. © 2016 IUBMB Life, 68(10):799-805, 2016.

Jiang YY, Lin DC, Mayakonda A, et al.
Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma.
Gut. 2017; 66(8):1358-1368 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
OBJECTIVES: Oesophageal squamous cell carcinoma (OSCC) is an aggressive malignancy and the major histological subtype of oesophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of OSCC, few targetable genomic lesions have been identified, and no molecular therapy is available. This study aims to identify druggable candidates in this tumour.
DESIGN: High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) were conducted to decipher the mechanisms of action of CDK7 inhibition in OSCC. A variety of in vitro and in vivo cellular assays were performed to determine the effects of candidate genes on OSCC malignant phenotypes.
RESULTS: The unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti-OSCC compound, THZ1, a specific CDK7 inhibitor. RNA-Seq revealed that low-dose THZ1 treatment caused selective inhibition of a number of oncogenic transcripts. Notably, further characterisation of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with super-enhancer (SE). Moreover, SE analysis alone uncovered many OSCC lineage-specific master regulators. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel OSCC oncogenes, including PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase.
CONCLUSIONS: Our integrative approaches led to a catalogue of SE-associated master regulators and oncogenic transcripts, which may significantly promote both the understanding of OSCC biology and the development of more innovative therapies.

Karpeta A, Maniecka A, Gregoraszczuk EŁ
Different mechanisms of action of 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) and its metabolites (5-OH-BDE-47 and 6-OH-BDE-47) on cell proliferation in OVCAR-3 ovarian cancer cells and MCF-7 breast cancer cells.
J Appl Toxicol. 2016; 36(12):1558-1567 [PubMed] Related Publications
Data concerning the possible action of polybrominated diphenyl ethers (PBDEs) in hormone-dependent cancer are scarce. Some data showed that PBDEs may directly affect breast cancer cells formation and only one research showed increased proliferation of the OVCAR-3 cells, but the results are ambiguous and the mechanisms are not clear. There is growing evidence that not only parent compounds but also its metabolites may be involved in cancer development. The present study was, therefore, designed to determine the effect of BDE-47 and its metabolites (2.5 to 50 ng ml

Pelish HE, Liau BB, Nitulescu II, et al.
Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
Nature. 2015; 526(7572):273-276 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.

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