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TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling

Author

Listed:
  • Rongxuan Zhu

    (Shanghai Jiao Tong University School of Medicine)

  • Olivier Gires

    (Ludwig-Maximilians-University of Munich)

  • Liqun Zhu

    (Liyang People’s Hospital)

  • Jun Liu

    (Shanghai Jiao Tong University School of Medicine)

  • Junjian Li

    (Shanghai Jiao Tong University School of Medicine)

  • Hao Yang

    (Shanghai University of Medicine and Health Sciences)

  • Gaoda Ju

    (Shanghai Jiao Tong University School of Medicine)

  • Jing Huang

    (Dalian University of Technology)

  • Weiyu Ge

    (Shanghai Jiao Tong University School of Medicine)

  • Yi Chen

    (Chinese Academy of Sciences)

  • Zhimin Lu

    (Zhejiang University School of Medicine)

  • Hongxia Wang

    (Shanghai Jiao Tong University School of Medicine)

Abstract

Cancer stem cells (CSCs) represent a major source of treatment resistance and tumor progression. However, regulation of CSCs stemness is not entirely understood. Here, we report that TSPAN8 expression is upregulated in breast CSCs, promotes the expression of the stemness gene NANOG, OCT4, and ALDHA1, and correlates with therapeutic resistance. Mechanistically, TSPAN8 interacts with PTCH1 and inhibits the degradation of the SHH/PTCH1 complex through recruitment of deubiquitinating enzyme ATXN3. This results in the translocation of SMO to cilia, downstream gene expression, resistance of CSCs to chemotherapeutic agents, and enhances tumor formation in mice. Accordingly, expression levels of TSPAN8, PTCH1, SHH, and ATXN3 are positively correlated in human breast cancer specimens, and high TSPAN8 and ATXN3 expression levels correlate with poor prognosis. These findings reveal a molecular basis of TSPAN8-enhanced Sonic Hedgehog signaling and highlight a role for TSPAN8 in promoting cancer stemness.

Suggested Citation

  • Rongxuan Zhu & Olivier Gires & Liqun Zhu & Jun Liu & Junjian Li & Hao Yang & Gaoda Ju & Jing Huang & Weiyu Ge & Yi Chen & Zhimin Lu & Hongxia Wang, 2019. "TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10739-3
    DOI: 10.1038/s41467-019-10739-3
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