Targeting transcription cycles in cancer

Vervoort, Stephin J.; Devlin, Jennifer R.; Kwiatkowski, Nicholas; Teng, Mingxing; Gray, Nathanael S.; Johnstone, Ricky W.

doi:10.1038/s41568-021-00411-8

Cited by 79 publications

(81 citation statements)

References 275 publications

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“…The post-initiation process of RNA Pol II progression is immediately interrupted, causing a pause state. The kinase activity of CDK9 is activated by binding to cyclin T, forming the positive transcription elongation factor b (P-TEFb), which selectively phosphorylates the CTD of RNA Pol II and the negative elongation factor (NELF), promoting the release of RNA Pol II pausing, resulting in transcript elongation [ 17 , 18 ]. CDK12 and CDK13 both partner with cyclin K, thereafter establishing a specific phosphorylation pattern of the CTD of RNA-Pol II, revealing progressed transcription elongation of full-length mRNA by prevention of intronic polyadenylation [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors

Funke

Düster

Wilson

et al. 2022

Cancers

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Type II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15% of patients with metastatic non-seminomas show cisplatin resistance and a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) have been shown to be effective targets in the treatment of different types of cancer. Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531. An XTT viability assay revealed a strong cytotoxic impact of CDK7/12/13 inhibitor SY0351 and CDK9 inhibitor NVP2 on the TGCT wild-type cell lines (2102EP, NCCIT, TCam2) and the cisplatin-resistant cell lines (2102EP-R, NCCIT-R). The CDK7 inhibitor YKL-5-124 showed a strong impact on 2102EP, 2102EP-R, NCCIT and NCCIT-R cell lines, leaving the MPAF control cell line mostly unaffected. FACS-based analysis revealed mild effects on the cell cycle of 2102EP and TCam2 cells after SY0351, YKL-5-124 or NVP2 treatment. Molecular analysis showed a cell-line-specific response for SY0351 and NVP2 inhibition while YKL-5-124 induced similar molecular changes in 2102EP, TCam2 and MPAF cells. Thus, after TGCT subtype determination, CDK inhibitors might be a potential alternative for optimized and individualized therapy independent of chemotherapy sensitivity.

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Section: Introductionmentioning

confidence: 99%

Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors

Funke

Düster

Wilson

et al. 2022

Cancers

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“…Conversely, an increase of SIRT1 histone deacetylase activity should be paralleled by reduced KAT7 acetylation together with an increase its histone acetyltransferase activity. In this way, the interplay between SIRT1 and KAT7 constitutes a novel rheostat mechanism regulating the total epigenetic output in terms of histone acetylation levels, which is reminiscent of other well-described relevant feedback mechanisms, such as the tightly regulated interplay between protein kinases and phosphatases in mitosis and beyond (80)(81)(82). Thus, while our data unveils a SIRT1-KAT7 link with clear relevance in T-cell leukemia, our results point to the existence of deacetylase-histone acetyltransferase balancing mechanisms which might be broadly relevant across different biological processes and cancer types.…”

Section: Discussionmentioning

confidence: 99%

A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

Lancho

Singh

Silva-Diz

et al. 2022

Preprint

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T-cell Acute Lymphoblastic Leukemia (T-ALL) is a NOTCH1-driven disease in need of novel therapies. Here, we identify a NOTCH1-SIRT1-KAT7 link as a therapeutic vulnerability in T-ALL, in which SIRT1 is overexpressed downstream of a novel NOTCH1-bound enhancer. SIRT1 loss impairs leukemia generation, while SIRT1 overexpression accelerates leukemia and confers resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, secondary SIRT1 loss extends survival and synergizes with NOTCH1 inhibition. Global acetyl-proteomics upon SIRT1 loss uncovered hyperacetylation of KAT7 and BRD1, subunits of a histone acetyltransferase complex targeting H4K12. Metabolic and gene expression profiling revealed a metabolic crisis together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a non-acetylatable KAT7 mutant partly rescued SIRT1 loss-induced proliferation defects. The newly unveiled NOTCH1-SIRT1-KAT7 axis uncovers novel therapeutic targets in T-ALL and reveals a circular feedback mechanism balancing deacetylase/acetyltransferase activation with potentially broad relevance in cancer.

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“…The closely related kinase Cdk11 was found to be important for splicing and the expression of histone genes [ 11 , 12 ], whereas Cdk12 plays a selective role in the expression of DNA damage response genes [ 13 , 14 ]. The multiple stages of transcription regulation controlled by CDKs have made them a promising target for cancer therapy [ 15 ]. The role of Cdk10 instead is not yet well defined.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of the human Cdk10/Cyclin Q complex

Düster

Pan

et al. 2022

Open Biol.

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Cyclin-dependent kinases (CDKs) are key players in cell cycle regulation and transcription. The CDK-family member Cdk10 is important for neural development and can act as a tumour suppressor, but the underlying molecular mechanisms are largely unknown. Here, we provide an in-depth analysis of Cdk10 substrate specificity and function. Using recombinant Cdk10/CycQ protein complexes, we characterize RNA pol II CTD, c-MYC and RB1 as in vitro protein substrates. Using an analogue-sensitive mutant kinase, we identify 89 different Cdk10 phosphosites in HEK cells originating from 66 different proteins. Among these, proteins involved in cell cycle, translation, stress response, growth signalling, as well as rRNA, and mRNA transcriptional regulation, are found. Of a set of pan-selective CDK- and Cdk9-specific inhibitors tested, all inhibited Cdk10/CycQ at least five times weaker than their proposed target kinases. We also identify Cdk10 as an in vitro substrate of Cdk1 and Cdk5 at multiple sites, allowing for a potential cross-talk between these CDKs. With this functional characterization, Cdk10 adopts a hybrid position in both cell cycle and transcriptional regulation.

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Targeting transcription cycles in cancer

Cited by 79 publications

References 275 publications

Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors

Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors

A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

Functional characterization of the human Cdk10/Cyclin Q complex

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