2. Academic Validation
  3. STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency

STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency

  • Cell Chem Biol. 2025 Oct 22:S2451-9456(25)00306-X. doi: 10.1016/j.chembiol.2025.10.001.
Zhengjin He 1,  Shishuang Chen 1,  Jinlong Suo 2,  Kai Xia 3,  Mingxian Liu 1,  Jingchuan Ma 1,  Yankai Chu 1,  Chao Wang 1,  Yueru Xie 1,  Wei Jiang 4,  Hui Du 5,  Shiyang Chen 4,  Zhilei Zhou 5,  Man Li 6,  Qing Wei 6,  Yun Zhao 7,  Jianfeng Chen 8,  Lin Li 8,  Yi Zeng 9,  Weiguo Zou 1,  Moubin Lin 10,  Hai Jiang 11
Affiliations

Affiliations

  • 1 Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
  • 3 Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China; Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai, China.
  • 4 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 5 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
  • 6 Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 7 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, P.R. China.
  • 8 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
  • 9 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 10 Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China; Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai, China. Electronic address: 1500142@tongji.edu.cn.
  • 11 Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: hai@sibcb.ac.cn.
PMID: 41130209 DOI: 10.1016/j.chembiol.2025.10.001
Abstract

Abnormalities in the Wnt pathway are major drivers of Cancer. RNF43 loss-of-function mutations are frequently detected in aggressive cancers lacking targeted therapies, underscoring the need to uncover key regulators and targets of this pathway. Using a double death trap (DDT) Wnt reporter and genome-wide CRISPR screen, we identified STT3A as an essential regulator of Wnt signaling. Genetic and pharmacological inhibition of STT3A suppressed aberrant Wnt activity caused by RNF43/ZNRF3 loss. Importantly, suppression of STT3A blocked the growth of RNF43-deficient Cancer cell lines, patient-derived organoids, and spontaneous tumors. Mechanistically, STT3A regulates Wnt/β-catenin signaling via LRP6, but not LRP5. Glycosylation of LRP6 by STT3A is required for Wnt ligand binding. Notably, STT3A depletion displayed milder effects on bone homeostasis, as supported by phenotypes in STT3A-deficient patients. Together, this study established STT3A as a critical Wnt regulator through LRP6 glycosylation and a therapeutic target for RNF43-deficient cancers.

Keywords

LRP6 glycosylation; RNF43-deficient cancers; STT3A; Wnt signaling; therapeutic target.

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