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Peer-reviewedCC BYCell discovery

FAM50A promotes esophageal squamous cell carcinoma progression via splicing-dependent oncogenic circSDK1- and DUSP22-mediated MAPK/FAK activation.

  • Yan Bian1,2,3
  • Ye Gao1,2,3
  • Xin Chang1,2,3
  • Bo Tian4
  • Qianqian Meng1,2,3
  • Lei Xin1,2,3
  • Han Lin5,6,7
  • Wei Wang8,9,10
  • Zhaoshen Li11,12,13
  • Luowei Wang14,15,16
16 affiliations
  1. 1Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.
  2. 2Changhai Clinical Research Unit, Changhai hospital, Naval Medical University, Shanghai, China.
  3. 3National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China.
  4. 4Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  5. 5Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China. [email protected].
  6. 6Changhai Clinical Research Unit, Changhai hospital, Naval Medical University, Shanghai, China. [email protected].
  7. 7National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. [email protected].
  8. 8Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China. [email protected].
  9. 9Changhai Clinical Research Unit, Changhai hospital, Naval Medical University, Shanghai, China. [email protected].
  10. 10National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. [email protected].
  11. 11Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China. [email protected].
  12. 12Changhai Clinical Research Unit, Changhai hospital, Naval Medical University, Shanghai, China. [email protected].
  13. 13National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. [email protected].
  14. 14Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China. [email protected].
  15. 15Changhai Clinical Research Unit, Changhai hospital, Naval Medical University, Shanghai, China. [email protected].
  16. 16National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. [email protected].
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Abstract

Dysregulated splicing factors play critical roles in tumor progression. Here, we identify family with sequence similarity 50 member A (FAM50A) as a pivotal oncogenic splicing factor involved in esophageal squamous cell carcinoma (ESCC). Multi-omics and multi-cohort analyses revealed that FAM50A is upregulated in ESCC and correlates with a poor prognosis. Functional studies demonstrated that FAM50A promotes ESCC proliferation and migration both in vitro and in vivo, primarily through the activation of mitogen-activated protein kinases (MAPKs) and focal adhesion kinase (FAK). We further characterized the FAM50A-binding RNA motif and established its transcriptome-wide splicing landscape. Notably, we identified a novel FAM50A-dependent backsplicing event that generates circSDK1, which originates from exons 2-4 of the sidekick cell adhesion molecule 1 (SDK1) pre-mRNA. Mechanistically, circSDK1 binds to dual-specificity phosphatase 22 (DUSP22) and occupies its phosphatase domain, inhibiting the DUSP22-mediated dephosphorylation of MAPKs and FAK and thereby sustaining their activation. Furthermore, the transcription factor TFAP2C increased FAM50A expression. Finally, we identified rifabutin as a small-molecule inhibitor of FAM50A and confirmed its anti-tumor efficacy in cell-derived xenograft, patient-derived organoid, and patient-derived xenograft models. In summary, FAM50A promotes ESCC progression via the FAM50A/circSDK1/DUSP22 axis, leading to MAPKs and FAK activation. Genetic or pharmacological targeting of FAM50A with rifabutin represents a promising therapeutic strategy for ESCC.

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Cite

BibTeXRIS
BibTeX
@article{bian2026fam50a,
  title = {{FAM50A promotes esophageal squamous cell carcinoma progression via splicing-dependent oncogenic circSDK1- and DUSP22-mediated MAPK/FAK activation.}},
  author = {Yan Bian and Ye Gao and Xin Chang and Bo Tian and Qianqian Meng and Lei Xin and Han Lin and Wei Wang and Zhaoshen Li and Luowei Wang},
  journal = {Cell discovery},
  year = {2026},
  month = oct,
  doi = {10.1038/s41421-026-00927-z},
  url = {https://europepmc.org/article/MED/42897138},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - FAM50A promotes esophageal squamous cell carcinoma progression via splicing-dependent oncogenic circSDK1- and DUSP22-mediated MAPK/FAK activation.
AU  - Yan Bian
AU  - Ye Gao
AU  - Xin Chang
AU  - Bo Tian
AU  - Qianqian Meng
AU  - Lei Xin
AU  - Han Lin
AU  - Wei Wang
AU  - Zhaoshen Li
AU  - Luowei Wang
PY  - 2026
DA  - 2026/10/20
JO  - Cell discovery
DO  - 10.1038/s41421-026-00927-z
UR  - https://europepmc.org/article/MED/42897138
AB  - Dysregulated splicing factors play critical roles in tumor progression. Here, we identify family with sequence similarity 50 member A (FAM50A) as a pivotal oncogenic splicing factor involved in esophageal squamous cell carcinoma (ESCC). Multi-omics and multi-cohort analyses revealed that FAM50A is upregulated in ESCC and correlates with a poor prognosis. Functional studies demonstrated that FAM50A promotes ESCC proliferation and migration both in vitro and in vivo, primarily through the activation of mitogen-activated protein kinases (MAPKs) and focal adhesion kinase (FAK). We further characterized the FAM50A-binding RNA motif and established its transcriptome-wide splicing landscape. Notably, we identified a novel FAM50A-dependent backsplicing event that generates circSDK1, which originates from exons 2-4 of the sidekick cell adhesion molecule 1 (SDK1) pre-mRNA. Mechanistically, circSDK1 binds to dual-specificity phosphatase 22 (DUSP22) and occupies its phosphatase domain, inhibiting the DUSP22-mediated dephosphorylation of MAPKs and FAK and thereby sustaining their activation. Furthermore, the transcription factor TFAP2C increased FAM50A expression. Finally, we identified rifabutin as a small-molecule inhibitor of FAM50A and confirmed its anti-tumor efficacy in cell-derived xenograft, patient-derived organoid, and patient-derived xenograft models. In summary, FAM50A promotes ESCC progression via the FAM50A/circSDK1/DUSP22 axis, leading to MAPKs and FAK activation. Genetic or pharmacological targeting of FAM50A with rifabutin represents a promising therapeutic strategy for ESCC.
SN  - 2056-5968
ER  -