SRPK1 acetylation modulates alternative splicing to regulate cisplatin resistance in breast cancer cells

Abstract

Cisplatin and other platinum-based compounds are frequently used to treat breast cancer, but their utility is severely compromised by drug resistance. Many genes dictating drug responsiveness are subject to pre-mRNA alternative splicing which is regulated by key kinases such as the serine-arginine protein kinase 1 (SRPK1). However, its contribution to drug resistance remains controversial. In this study, we have identified that Tip60-mediated acetylation of SRPK1 is closely associated with chemotherapy sensitivity. In breast cancer cells, cisplatin induced SRPK1 acetylation but in the corresponding resistant cells, it reduced acetylation yet increased phosphorylation and kinase activity of SRPK1, favouring the splicing of some anti-apoptotic variants. Significantly, the cisplatin-resistant cells could be resensitized by enhancing SRPK1 acetylation or inhibiting its kinase activity. Hence, our study reveals a key role of SRPK1 in the development of cisplatin resistance in breast cancer cells and suggests a potential therapeutic avenue for overcoming chemotherapy resistance.

RNA splicing alteration in the response to platinum chemotherapy in ovarian cancer: A possible biomarker and therapeutic target

“…More recently, it has been shown that PT also induced the acetylation of the serine‐arginine protein kinase 1 (SRPK1). SRPK1 acetylation was associated with its cytoplasmic localization and PT sensitivity 67 . Conversely, in PT‐resistant breast cancer cells, PT treatment reduced SRPK1 acetylation favoring the expression of antiapoptotic splicing variants of several genes 67 .…”

“…SRPK1 acetylation was associated with its cytoplasmic localization and PT sensitivity. 67 Conversely, in PT-resistant breast cancer cells, PT treatment reduced SRPK1 acetylation favoring the expression of antiapoptotic splicing variants of several genes. 67 These evidences are in good accord with the general knowledge that HDACs interact with the spliceosome and participate in the control of the acetylation states of splicing factors.…”

“…68 Thus, converging evidences suggest that PT-treatment directly regulates acetylation and phosphorylation of SRSF2 and SRPK1 which had opposite effects on their protein stability and subcellular localization. 59,67 In this way PT could directly regulate the splicing activity.…”

MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets

“…This results in a decrease in the kinase activity of SRPK1, changes in the stability of this protein and, therefore, changes in its ability to regulate alternative splicing. This increase in the acetylation of SRPK1 is accompanied by an increase in the sensitivity of breast cancers to cisplatin [ 49 ]. Doxorubicin is a widely used chemotherapeutic agent for the treatment of breast cancer.…”

Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy

“…The targeting of the splicing process of myeloid cell leukemia-1 along with other apoptotic regulators is a new therapeutic target in breast cancer cells and provides an effective way to overcome therapy resistance in these cells [ 69 ]. Tip60-mediated acetylation of serine-arginine protein kinase 1 is closely associated with chemotherapy sensitivity [ 70 ]. In breast cancer cells, Cisplatin induces this acetylation pattern while in the corresponding resistant cells, it reduces acetylation.…”