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Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells

Overview of attention for article published in BMC Cancer, April 2018
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Title
Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells
Published in
BMC Cancer, April 2018
DOI 10.1186/s12885-018-4227-7
Pubmed ID
Authors

Elizabeth Bowler, Sean Porazinski, Simon Uzor, Philippe Thibault, Mathieu Durand, Elvy Lapointe, Kasper M. A. Rouschop, John Hancock, Ian Wilson, Michael Ladomery

Abstract

Mounting evidence suggests that one of the ways that cells adapt to hypoxia is through alternative splicing. The aim of this study was firstly to examine the effect of hypoxia on the alternative splicing of cancer associated genes using the prostate cancer cell line PC3 as a model. Secondly, the effect of hypoxia on the expression of several regulators of splicing was examined. PC3 cells were grown in 1% oxygen in a hypoxic chamber for 48 h, RNA extracted and sent for high throughput PCR analysis at the RNomics platform at the University of Sherbrooke, Canada. Genes whose exon inclusion rate PSI (ψ) changed significantly were identified, and their altered exon inclusion rates verified by RT-PCR in three cell lines. The expression of splice factors and splice factor kinases in response to hypoxia was examined by qPCR and western blotting. The splice factor kinase CLK1 was inhibited with the benzothiazole TG003. In PC3 cells the exon inclusion rate PSI (ψ) was seen to change by > 25% in 12 cancer-associated genes; MBP, APAF1, PUF60, SYNE2, CDC42BPA, FGFR10P, BTN2A2, UTRN, RAP1GDS1, PTPN13, TTC23 and CASP9 (caspase 9). The expression of the splice factors SRSF1, SRSF2, SRSF3, SAM68, HuR, hnRNPA1, and of the splice factor kinases SRPK1 and CLK1 increased significantly in hypoxia. We also observed that the splice factor kinase CLK3, but not CLK2 and CLK4, was also induced in hypoxic DU145 prostate, HT29 colon and MCF7 breast cancer cell lines. Lastly, we show that the inhibition of CLK1 in PC3 cells with the benzothiazole TG003 increased expression of the anti-apoptotic isoform caspase 9b. Significant changes in alternative splicing of cancer associated genes occur in prostate cancer cells in hypoxic conditions. The expression of several splice factors and splice factor kinases increases during hypoxia, in particular the Cdc-like splice factor kinases CLK1 and CLK3. We suggest that in hypoxia the elevated expression of these regulators of splicing helps cells adapt through alternative splicing of key cancer-associated genes. We suggest that the CLK splice factor kinases could be targeted in cancers in which hypoxia contributes to resistance to therapy.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 25 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 25 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 7 28%
Researcher 5 20%
Student > Bachelor 4 16%
Unspecified 4 16%
Other 2 8%
Other 3 12%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 11 44%
Unspecified 5 20%
Agricultural and Biological Sciences 5 20%
Medicine and Dentistry 3 12%
Engineering 1 4%
Other 0 0%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 11 April 2018.
All research outputs
#10,622,363
of 13,345,024 outputs
Outputs from BMC Cancer
#3,310
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Outputs of similar age
#202,881
of 270,000 outputs
Outputs of similar age from BMC Cancer
#1
of 2 outputs
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