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

Belali, Tareg; Wodi, Chigeru; Clark, Bethany; Cheung, Man Kim; Craig, Tim J.; Wheway, Gabrielle; Wagner, Nicole; Wagner, Kay Dietrich; Roberts, Stefan; Porazinski, Sean; Ladomery, Michael

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 VEGF165b splice isoform. We propose that by upregulating SRPK1 transcription WT1 can direct an alternative splicing landscape that facilitates tumour growth.

• Journal Article Type: Article
• Acceptance Date: Sep 24, 2020
• Online Publication Date: Oct 2, 2020
• Publication Date: Dec 1, 2020
• Deposit Date: Oct 23, 2020
• Publicly Available Date: Oct 3, 2021
• Journal: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
• Print ISSN: 1874-9399
• Electronic ISSN: 1876-4320
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 1863
• Issue: 12
• Article Number: 194642
• DOI: https://doi.org/10.1016/j.bbagrm.2020.194642
• Keywords: Splice factor, kinases, SRPK1, SRSF1, WT1, BASP1, VEGF
• Public URL: https://uwe-repository.worktribe.com/output/6749614