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.

异常剪接的剪接在所有癌症特征中都起着重要作用。剪接因子激酶SRPK1驱动致癌剪接因子（如SRSF1）的活性。SRSF1继而促进有利于肿瘤生长的剪接同工型的表达，包括促血管生成的VEGF。在K562白血病和PC3前列腺癌细胞系中对SRPK1进行基因敲除（使用siRNA）或化学抑制（使用SPHINX）可减少细胞增殖，侵袭和迁移。在肾小球足细胞中，Wilms肿瘤抑制因子锌指转录因子WT1抑制SRPK1转录。在这里，我们表明在癌细胞中WT1激活SRPK1转录，除非邻近转录起始位点的规范WT1结合位点发生突变。WT1激活SRPK1的能力转录共抑制因子BASP1逆转了转录，WT1和BASP1都与SRPK1启动子共沉淀。BASP1显着增加了抗血管生成VEGF ₁₆₅ b剪接同工型的表达。我们建议通过上调SRPK1转录，WT1可以指导另一种促进肿瘤生长的剪接景观。