Sun Qi, Tang Yun, Wang Lian, Liu Boxin, Xiao Jianhong, Wang Hanbin, Lei Shujing, Chen Yuexuan, Liu Yi, Liu Shanshan, Zhao Xibao, Zhang Jitian, Lu Desheng
Guangdong Provincial Key Laboratory of Regional Immunity and Disease, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China.
Guangdong Provincial Key Laboratory of Regional Immunity and Disease, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China.
J Biol Chem. 2025 Jul 21;301(9):110508. doi: 10.1016/j.jbc.2025.110508.
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.
Bcl-x可变剪接的失调与肿瘤发生和化疗耐药相关。然而，Bcl-x剪接的潜在分子机制仍未完全明确。在此，我们证明酪蛋白激酶1ε（CK1ε）参与了Bcl-x可变剪接的调控。首先，我们注意到，特异性CK1δ/ε抑制剂SR3029以剂量依赖的方式有效降低了Bcl-xL的mRNA和蛋白表达，并伴随着Bcl-xS的mRNA和蛋白水平升高。与对照细胞相比，CK1ε的过表达降低了Bcl-xS/Bcl-xL mRNA和蛋白的比例，而CK1ε的缺失则导致Bcl-xS/Bcl-xL比例增加。CK1ε的过表达还消除了富含丝氨酸/精氨酸的剪接因子10（SRSF10）敲低对Bcl-xS/Bcl-xL比例的影响。随后，发现CK1ε与SRSF10相互作用，并在S23和S133位点磷酸化SRSF10，这可能是SRSF10与Bcl-xL mRNA结合所必需的。此外，SRSF10的缺失显著促进了肺癌细胞的凋亡，并抑制了其活力、增殖和集落形成。CK1δ/ε抑制剂SR3029可进一步增强沉默SRSF10对生物学行为的影响。肺癌细胞异种移植模型证实，对CK1ε的药理学抑制和SRSF10的敲低协同抑制肿瘤生长。综上所述，我们的结果揭示了一种新的机制，即CK1ε/SRSF10轴调节Bcl-x前体mRNA的可变剪接，这可能是肺癌潜在的治疗靶点。
