DUSP4 promotes esophageal squamous cell carcinoma progression by dephosphorylating HSP90β
Liting Zhou,
Ning Yao,
Lu Yang,
Kangdong Liu,
Yan Qiao,
Chuntian Huang,
Ruijuan Du,
Yiu To Yeung,
Wenting Liu,
Dan Cheng,
Zigang Dong,
Xiang Li
Affiliations
Liting Zhou
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
Ning Yao
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
Lu Yang
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
Kangdong Liu
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
Yan Qiao
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
Chuntian Huang
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
Ruijuan Du
Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang 473004, China
Yiu To Yeung
China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
Wenting Liu
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
Dan Cheng
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
Zigang Dong
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; Corresponding author
Xiang Li
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; Corresponding author
Summary: 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.
