Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells

Recasens, Ariadna; Humphrey, Sean J.; Ellis, Michael; Hoque, Monira; Abbassi, Ramzi H.; Chen, Brianna; Longworth, Mitchell; Needham, Elise J.; James, David E.; Johns, Terrance G.; Day, Bryan W.; Kassiou, Michael; Yang, Pengyi; Munoz, Lenka

doi:10.1038/s41420-021-00456-6

Cited by 41 publications

(42 citation statements)

References 53 publications

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“…Increases in cyclin D1 and pRb were observed, two factors involved in initiating the cell cycle, but this was counterbalanced by an increase in the cell cycle inhibitors p21 and p27. A recent paper by Recasens and colleagues 38 suggests that DYRK1A can induce cyclin B1 degradation and thereby control the activity of CDK1. Complete DYRK1A inhibition, as would be expected here with VER‐239353, resulted in cyclin B1 stabilization and accumulation in glioblastoma cells leading to CDK1 inhibition and cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

Targeting DYRK1A/B kinases to modulate p21‐cyclin D1‐p27 signalling and induce anti‐tumour activity in a model of human glioblastoma

Massey¹,

Benwell²,

Burbridge

et al. 2021

J Cellular Molecular Medi

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The dual‐specificity tyrosine‐regulated kinases DYRK1A and DYRK1B play a key role in controlling the quiescence‐proliferation switch in cancer cells. Serum reduction of U87MG 2D cultures or multi‐cellular tumour spheroids induced a quiescent like state characterized by increased DYRK1B and p27, and decreased pRb and cyclin D1. VER‐239353 is a potent, selective inhibitor of the DYRK1A and DYRK1B kinases identified through fragment and structure‐guided drug discovery. Inhibition of DYRK1A/B by VER‐239353 in quiescent U87MG cells increased pRb, DYRK1B and cyclin D1 but also increased the cell cycle inhibitors p21 and p27. This resulted in exit from G0 but subsequent arrest in G1. DYRK1A/B inhibition reduced the proliferation of U87MG cells in 2D and 3D culture with greater effects observed under reduced serum conditions. Paradoxically, the induced re‐expression of cell cycle proteins by DYRK1A/B inhibition further inhibited cell proliferation. Cell growth arrest induced in quiescent cells by DYRK1A/B inhibition was reversible through the addition of growth‐promoting factors. DYRK inhibition‐induced DNA damage and synergized with a CHK1 inhibitor in the U87MG spheroids. In vivo, DYRK1A/B inhibition‐induced tumour stasis in a U87MG tumour xenograft model. These results suggest that further evaluation of VER‐239353 as a treatment for glioblastoma is therefore warranted.

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Section: Discussionmentioning

confidence: 99%

Targeting DYRK1A/B kinases to modulate p21‐cyclin D1‐p27 signalling and induce anti‐tumour activity in a model of human glioblastoma

Massey¹,

Benwell²,

Burbridge

et al. 2021

J Cellular Molecular Medi

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“…Our results are also limited to in vitro cellular experiments confirming that the knockout or targeted inhibition of DYRK1A has an efficient radiosensitizing effect. Despite the widespread use of Harmine as a targeted inhibitor of DYRK1A, its further clinical application is limited by its poor specificity and potential side effects, and further in vivo experiments are still needed to further elucidate the specific mechanisms by which Harmine directly induces DNA damage and participates in DDR inhibition [ 46 ]. Our results highlight the need for additional clinical trials to evaluate this newly discovered therapeutic combination in the treatment of patients with PDAC and other malignancies.…”

Section: Discussionmentioning

confidence: 99%

CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer

Lan

Zeng

Zhang

et al. 2022

Cancers

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Although radiation therapy has recently made great advances in cancer treatment, the majority of patients diagnosed with pancreatic cancer (PC) cannot achieve satisfactory outcomes due to intrinsic and acquired radioresistance. Identifying the molecular mechanisms that impair the efficacy of radiotherapy and targeting these pathways are essential to improve the radiation response of PC patients. Our goal is to identify sensitive targets for pancreatic cancer radiotherapy (RT) using the kinome-wide CRISPR-Cas9 loss-of-function screen and enhance the therapeutic effect through the development and application of targeted inhibitors combined with radiotherapy. We transduced pancreatic cancer cells with a protein kinase library; 2D and 3D library cells were irradiated daily with a single dose of up to 2 Gy for 4 weeks for a total of 40 Gy using an X-ray generator. Sufficient DNA was collected for next-generation deep sequencing to identify candidate genes. In this study, we identified several cell cycle checkpoint kinases and DNA damage related kinases in 2D- and 3D-cultivated cells, including DYRK1A, whose loss of function sensitizes cells to radiotherapy. Additionally, we demonstrated that the harmine-targeted suppression of DYRK1A used in conjunction with radiotherapy increases DNA double-strand breaks (DSBs) and impairs homologous repair (HR), resulting in more cancer cell death. Our results support the use of CRISPR-Cas9 screening to identify new therapeutic targets, develop radiosensitizers, and provide novel strategies for overcoming the tolerance of pancreatic cancer to radiotherapy.

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“…To evaluate the stability of SPSs, we obtained three independent phosphoproteomic datasets, which are not included in the 53 datasets used for SPS identification. These include a human glioblastoma profiling dataset ( Recasens et al , 2021 ) that measures the responses of treatments to glioblastoma cells, and two mouse datasets that profiles mouse embryonic stem cell (ESC) differentiation ( Yang et al , 2019 ) and response of adipocytes to redox signaling ( Su et al , 2019 ), respectively. First, we compared SPSs with size-matched mid- and bottom-ranked sites ( n = 326), and sites that are not defined as SPSs (i.e.…”

Section: Methodsmentioning

confidence: 99%

“…The phosphoproteomic data described in this study are publicly available. In particular, the mouse ESC dataset ( Yang et al , 2019 ) (PRIDE: PXD010621), the human glioblastoma dataset ( Recasens et al , 2021 ) (PRIDE: PXD020441) and the mouse adipocyte dataset ( Su et al , 2019 ) (PRIDE: PXD011525) are used for evaluating the stability of selected SPSs. The human ESC dataset ( Billing et al , 2019 ) (PRIDE: PXD004652), the HCT116 dataset ( Hahn et al , 2021 ) (PRIDE: PXD023703), the T-cell dataset ( Martinez-Fabregas et al , 2020 ) (PRIDE: PXD020964) and the AGS cell dataset ( Yin et al , 2020 ) (PRIDE: PXD005093) are included for independent validation of the reproducibility of the proposed framework.…”

Section: Methodsmentioning

confidence: 99%

Functional analysis of the stable phosphoproteome reveals cancer vulnerabilities

Xiao¹,

Kim

Pang

et al. 2022

Bioinformatics

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Motivation The advance of mass spectrometry-based technologies enabled the profiling of the phosphoproteomes of a multitude of cell and tissue types. However, current research primarily focused on investigating the phosphorylation dynamics in specific cell types and experimental conditions, whereas the phosphorylation events that are common across cell/tissue types and stable regardless of experimental conditions are, so far, mostly ignored. Results Here, we developed a statistical framework to identify the stable phosphoproteome across 53 human phosphoproteomics datasets, covering 40 cell/tissue types and 194 conditions/treatments. We demonstrate that the stably phosphorylated sites (SPSs) identified from our statistical framework are evolutionarily conserved, functionally important, and enriched in a range of core signalling and gene pathways. Particularly, we show that SPSs are highly enriched in the RNA splicing pathway, an essential cellular process in mammalian cells, and frequently disrupted by cancer mutations, suggesting a link between the dysregulation of RNA splicing and cancer development through mutations on SPSs. Availability The source code for data analysis in this study is available from Github repository https://github.com/PYangLab/SPSs under the open-source license of GPL-3. The data used in this study are publicly available (see section ‘Data availability’). Supplementary information Supplementary data are available at Bioinformatics online.

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Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells

Cited by 41 publications

References 53 publications

Targeting DYRK1A/B kinases to modulate p21‐cyclin D1‐p27 signalling and induce anti‐tumour activity in a model of human glioblastoma

Targeting DYRK1A/B kinases to modulate p21‐cyclin D1‐p27 signalling and induce anti‐tumour activity in a model of human glioblastoma

CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer

Functional analysis of the stable phosphoproteome reveals cancer vulnerabilities

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