Sodium butyrate (NaBu) is a histone deacetylase inhibitor that exhibits numerous antiproliferative activities in various cancer cell lines, notably through the accumulation of the well-known cyclin-dependent kinase inhibitor p21(WAF1) . SRSF2 belongs to the family of SR proteins that are crucial regulators of constitutive and alternative pre-mRNA splicing. Previous studies demonstrated that NaBu alters pre-mRNA splicing patterns through upregulation of SR proteins expression in non-tumor cells. In this study, we show that NaBu also induces the accumulation of SRSF2 in human lung carcinoma cell lines. We recently identified a signaling network involving the acetyltransferase TIP60, the deacetylase HDAC6 and the SRPK kinases that regulates SRSF2 protein turnover through phosphorylation/acetylation modifications in response to cisplatin. Here, we show that the same signaling pathway controls SRSF2 protein expression upon NaBu treatment. Importantly, we further demonstrate that SRSF2 is required for the accumulation of p21(WAF1) at both mRNA and protein levels in response to NaBu. Finally, we provide evidence that a long-term NaBu-treatment triggers senescence in our cellular models, a phenomenon that is prevented by the knockdown of SRSF2. Altogether, these results unravel a new function of SRSF2 in the process of cellular senescence and identify the cyclin-Cdk inhibitor p21(WAF1) as a key target of SRSF2 in this setting.