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Casein kinase 2-mediated phosphorylation of the splicing factor SF3B3 plays a key role in esophageal squamous cell
Du-Chuang Wang1,2, Jia-Yuan Li1,2,3, Xiao-Bing Wang1,2
1State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China.
Abstract:
Protein kinases play a crucial role in regulating cellular processes, and their dysregulation is frequently implicated in various diseases, including cancer. Targeting protein kinases represents a promising therapeutic strategy for cancer treatment. Esophageal squamous cell carcinoma (ESCC) constitutes over 90% of esophageal cancer cases in high-incidence regions, with a global five-year survival rate below 20%. Here, we report that CK2 is aberrantly activated in ESCC, identified through kinase-substrate enrichment analysis (KSEA) of large-scale proteomic and phosphoproteomic data. Functional enrichment revealed the splicing factor SF3B3 as a clinically relevant CK2 substrate. We demonstrated that CK2-mediated phosphorylation of SF3B3 T1200 plays a pivotal role in ESCC progression. Mechanistically, CK2-mediated phosphorylation of SF3B3 enhances its affinity for the deubiquitinase USP7, leading to SF3B3 deubiquitination and subsequent protein stabilization. This stabilization drives ESCC progression by regulating alternative splicing (AS) events, including a critical event involving the inclusion of exon 4 in the EXOSC2 transcript. Furthermore, we demonstrated that SF3B3 T1200 phosphorylation specifically facilitates its incorporation into the U2 snRNP complex, directly promoting the aforementioned EXOSC2 exon 4 inclusion. Crucially, targeting CK2 or USP7, either individually or in combination, effectively suppressed ESCC progression. Our findings uncover a key molecular mechanism underlying SF3B3 stabilization and AS regulation, offering novel therapeutic opportunities for ESCC.
Insights
Aberrantly activated protein kinase CK2 phosphorylates splicing factor SF3B3, promoting esophageal squamous cell carcinoma (ESCC) progression. Targeting CK2 or USP7 offers new therapeutic strategies for ESCC.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Protein kinases are vital for cellular functions; their dysregulation contributes to diseases like cancer.
- Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, necessitating novel therapeutic targets.
- CK2 kinase is implicated in cancer, but its specific role in ESCC requires elucidation.
Purpose of the Study:
- To investigate the role of CK2 in ESCC pathogenesis.
- To identify and characterize CK2 substrates in ESCC.
- To explore therapeutic strategies targeting the CK2 pathway in ESCC.
Main Methods:
- Kinase-substrate enrichment analysis (KSEA) of proteomic and phosphoproteomic data.
- Functional enrichment analysis to identify key substrates.
- In vitro and in vivo experiments to validate molecular mechanisms and therapeutic efficacy.
Main Results:
- CK2 is aberrantly activated in ESCC.
- SF3B3 is identified as a key CK2 substrate, with phosphorylation at T1200 crucial for ESCC progression.
- CK2-mediated SF3B3 phosphorylation stabilizes SF3B3 by enhancing its interaction with USP7, promoting alternative splicing events like EXOSC2 exon 4 inclusion.
- Targeting CK2 or USP7 suppressed ESCC progression.
Conclusions:
- CK2-mediated SF3B3 phosphorylation is a critical driver of ESCC progression through alternative splicing regulation.
- The CK2-USP7-SF3B3 axis represents a novel therapeutic vulnerability in ESCC.
- Inhibition of CK2 or USP7 presents promising therapeutic avenues for ESCC treatment.
