s10ֽ𾺲 newbisystem.com Copyright © 2020. Published by Elsevier B.V." />

University of Southampton Institutional Repository

WT1 activates transcription of the splice factor kinase SRPK1 gene in PC3 and K562 cancer cells in the absence of corepressor BASP1

WT1 activates transcription of the splice factor kinase SRPK1 gene in PC3 and K562 cancer cells in the absence of corepressor BASP1
WT1 activates transcription of the splice factor kinase SRPK1 gene in PC3 and K562 cancer cells in the absence of corepressor BASP1

Dysregulated alternative splicing plays a prominent role in all hallmarks of cancer. The splice factor kinase SRPK1 drives the activity of oncogenic splice factors such as SRSF1. SRSF1 in turn promotes the expression of splice isoforms that favour tumour growth, including proangiogenic VEGF. Knockdown (with siRNA) or chemical inhibition (using SPHINX) of SRPK1 in K562 leukemia and PC3 prostate cancer cell lines reduced cell proliferation, invasion and migration. In glomerular podocytes, the Wilms tumour suppressor zinc-finger transcription factor WT1 represses SRPK1 transcription. Here we show that in cancer cells WT1 activates SRPK1 transcription, unless a canonical WT1 binding site adjacent to the transcription start site is mutated. The ability of WT1 to activate SRPK1 transcription was reversed by the transcriptional corepressor BASP1, and both WT1 and BASP1 co-precipitated with the SRPK1 promoter. BASP1 significantly increased the expression of the antiangiogenic VEGF 165b splice isoform. We propose that by upregulating SRPK1 transcription WT1 can direct an alternative splicing landscape that facilitates tumour growth.

BASP1, SRPK1, SRSF1, Splice factor kinases, VEGF, WT1
1874-9399
Belali, Tareg
6115e7ce-1e45-4cff-a8e3-699587936802
Wodi, Chigeru
fd802005-97e8-45d4-8ed3-8d6df692e0eb
Clark, Bethany
02827448-9a77-46c3-a809-d0d16eb7c7c1
Cheung, Man-Kim
8553ef1d-7690-4b23-b10a-5d89eca558c1
Craig, Tim J
30505243-6c76-4a59-91b4-2e743f8ebb14
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Wagner, Nicole
19477731-4e09-4f8b-bfbf-c8d0335f6193
Wagner, Kay-Dietrich
ca4513ef-33fd-41ce-b38c-c8bca256239e
Roberts, Stefan
c052aa0b-7c2c-4615-bf23-473f13a41ddb
Porazinski, Sean
f7235f83-1df6-4d73-9e43-00762c36e1c7
Ladomery, Michael
8ad82c83-972a-44ee-a7b5-9a150c497a58
Belali, Tareg
6115e7ce-1e45-4cff-a8e3-699587936802
Wodi, Chigeru
fd802005-97e8-45d4-8ed3-8d6df692e0eb
Clark, Bethany
02827448-9a77-46c3-a809-d0d16eb7c7c1
Cheung, Man-Kim
8553ef1d-7690-4b23-b10a-5d89eca558c1
Craig, Tim J
30505243-6c76-4a59-91b4-2e743f8ebb14
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Wagner, Nicole
19477731-4e09-4f8b-bfbf-c8d0335f6193
Wagner, Kay-Dietrich
ca4513ef-33fd-41ce-b38c-c8bca256239e
Roberts, Stefan
c052aa0b-7c2c-4615-bf23-473f13a41ddb
Porazinski, Sean
f7235f83-1df6-4d73-9e43-00762c36e1c7
Ladomery, Michael
8ad82c83-972a-44ee-a7b5-9a150c497a58

Belali, Tareg, Wodi, Chigeru, Clark, Bethany, Cheung, Man-Kim, Craig, Tim J, Wheway, Gabrielle, Wagner, Nicole, Wagner, Kay-Dietrich, Roberts, Stefan, Porazinski, Sean and Ladomery, Michael (2020) WT1 activates transcription of the splice factor kinase SRPK1 gene in PC3 and K562 cancer cells in the absence of corepressor BASP1. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1863 (12), [194642]. ().

Record type: Article

Abstract

Dysregulated alternative splicing plays a prominent role in all hallmarks of cancer. The splice factor kinase SRPK1 drives the activity of oncogenic splice factors such as SRSF1. SRSF1 in turn promotes the expression of splice isoforms that favour tumour growth, including proangiogenic VEGF. Knockdown (with siRNA) or chemical inhibition (using SPHINX) of SRPK1 in K562 leukemia and PC3 prostate cancer cell lines reduced cell proliferation, invasion and migration. In glomerular podocytes, the Wilms tumour suppressor zinc-finger transcription factor WT1 represses SRPK1 transcription. Here we show that in cancer cells WT1 activates SRPK1 transcription, unless a canonical WT1 binding site adjacent to the transcription start site is mutated. The ability of WT1 to activate SRPK1 transcription was reversed by the transcriptional corepressor BASP1, and both WT1 and BASP1 co-precipitated with the SRPK1 promoter. BASP1 significantly increased the expression of the antiangiogenic VEGF 165b splice isoform. We propose that by upregulating SRPK1 transcription WT1 can direct an alternative splicing landscape that facilitates tumour growth.

Full text not available from this repository.

More information

e-pub ahead of print date: 2 October 2020
Published date: December 2020
Additional Information: s10ֽ𾺲 newbisystem.com Copyright © 2020. Published by Elsevier B.V.
Keywords: BASP1, SRPK1, SRSF1, Splice factor kinases, VEGF, WT1

Identifiers

Local EPrints ID: 445120
URI: http://eprints.soton.ac.uk/id/eprint/445120
DOI:
ISSN: 1874-9399
PURE UUID: 86a7f670-9af8-4c93-b4fd-6b9d8359c1c5
ORCID for Gabrielle Wheway:

Catalogue record

Date deposited: 19 Nov 2020 17:33
Last modified: 19 Nov 2020 17:33

Export record

Altmetrics

Contributors

Author: Tareg Belali
Author: Chigeru Wodi
Author: Bethany Clark
Author: Man-Kim Cheung
Author: Tim J Craig
Author:
Author: Nicole Wagner
Author: Kay-Dietrich Wagner
Author: Stefan Roberts
Author: Sean Porazinski
Author: Michael Ladomery

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using , developed at the University of Southampton, but available to everyone to use.

If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×