2. Academic Validation
  3. DUSP4 promotes esophageal squamous cell carcinoma progression by dephosphorylating HSP90β

DUSP4 promotes esophageal squamous cell carcinoma progression by dephosphorylating HSP90β

  • Cell Rep. 2023 May 2;42(5):112445. doi: 10.1016/j.celrep.2023.112445.
Liting Zhou 1,  Ning Yao 1,  Lu Yang 1,  Kangdong Liu 2,  Yan Qiao 2,  Chuntian Huang 1,  Ruijuan Du 3,  Yiu To Yeung 4,  Wenting Liu 1,  Dan Cheng 1,  Zigang Dong 5,  Xiang Li 6
Affiliations

Affiliations

  • 1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China.
  • 2 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450000, China.
  • 3 Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang 473004, China.
  • 4 China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China.
  • 5 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450000, China. Electronic address: dongzg@zzu.edu.cn.
  • 6 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450000, China. Electronic address: lixiang@zzu.edu.cn.
PMID: 37141098 DOI: 10.1016/j.celrep.2023.112445
Abstract

The molecular and pathogenic mechanisms of esophageal squamous cell carcinoma (ESCC) development are still unclear, which hinders the development of effective treatments. In this study, we report that DUSP4 is highly expressed in human ESCC and is negatively correlated with patient prognosis. Knockdown of DUSP4 suppresses cell proliferation and patient-derived xenograft (PDX)-derived Organoid (PDXO) growth and inhibits cell-derived xenograft (CDX) development. Mechanistically, DUSP4 directly binds to heat shock protein isoform β (HSP90β) and promotes the ATPase activity of HSP90β by dephosphorylating HSP90β on T214 and Y216. These dephosphorylation sites are critical for the stability of JAK1/2-STAT3 signaling and p-STAT3 (Y705) nucleus translocation. In vivo, Dusp4 knockout in mice significantly inhibits 4-nitrochinoline-oxide-induced esophageal tumorigenesis. Moreover, DUSP4 lentivirus or treatment with HSP90β inhibitor (NVP-BEP800) significantly impedes PDX tumor growth and inactivates the JAK1/2-STAT3 signaling pathway. These data provide insight into the role of the DUSP4-HSP90β-JAK1/2-STAT3 axis in ESCC progression and describe a strategy for ESCC treatment.

Keywords

CP: Cancer; esophageal squamous cell carcinomal, DUSP4, HSP90β, dephosphorylation, JAK1/2-STAT3, NVP-BEP800.

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