Casein kinase 2-mediated phosphorylation of the splicing factor SF3B3 plays a key role in esophageal squamous cell carcinoma progression

  • PLoS Biol. 2026 Apr 10;24(4):e3003729. doi: 10.1371/journal.pbio.3003729.
Du-Chuang Wang  1  2 ,  Jia-Yuan Li  1  2  3 ,  Xiao-Bing Wang  1  2 ,  Guo-Sheng Hu  1  2 ,  Rui-Chao Nie  1  2  4 ,  Bin Zheng  5 ,  Yao-Hui He  1  2  6 ,  Wen Liu  1  2  4  7
Affiliations
  • 1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 2. Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 3. Jiangxi Health Industry Institute of Traditional Chinese Medicine, Nanchang, Jiangxi, China.
  • 4. National Institute for Data Science in Health and Medicine, Xiamen University, Xiang'an South Road, Xiamen, Fujian, China.
  • 5. Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
  • 6. Institute for Future Sciences, University of South China, Changsha, Hunan, China.
  • 7. Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong, China.
PMID: 41961893 DOI: 10.1371/journal.pbio.3003729
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.

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