CK1ε/SRSF10 axis regulates the alternative splicing of Bcl-x in lung cancer cells

The dysregulation of Bcl-x alternative splicing is associated with tumor development and chemoresistance. However, the underlying molecular mechanisms of Bcl-x splicing are still not well-defined. Here, we demonstrated that casein kinase 1ε (CK1ε) was involved in the regulation of Bcl-x alternative splicing. Initially, we noted that SR3029, a specific CK1δ/ε inhibitor, effectively reduced the mRNA and protein expression of Bcl-xL and accompanied by an increase in the mRNA and protein levels of Bcl-xS in a dose-dependent manner. Overexpression of CK1ε decreased the ratio of Bcl-xS/Bcl-xL mRNA and protein compared to the control cells, while depletion of CK1ε leads to an increase in the ratio of Bcl-xS/Bcl-xL. The overexpression of CK1ε also abrogated the impact of serine/arginine-rich splicing factor 10 (SRSF10) knockdown on the ratio of Bcl-xS/Bcl-xL. Subsequently, CK1ε was found to interact with SRSF10 and phosphorylate SRSF10 at S23 and S133, which may be required for the binding of SRSF10 to the Bcl-xL mRNA. Furthermore, depletion of SRSF10 markedly promoted apoptosis and inhibited the viability, proliferation, and colony formation in lung cancer cells. CK1δ/ε inhibitor SR3029 could further enhance the effect of silencing SRSF10 on biological behavior. The xenograft model of lung cancer cells confirmed that pharmacological inhibition of CK1ε and the knockdown of SRSF10 synergistically inhibited tumor growth. Taken together, our results revealed a novel mechanism by which the CK1ε/SRSF10 axis regulates the alternative splicing of the Bcl-x precursor mRNA, which may be a potential therapeutic target for lung cancer.