TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling

Rongxuan Zhu, Olivier Gires, Liqun Zhu, Jun Liu, Junjian Li, Hao Yang, Gaoda Ju, Jing Huang, Weiyu Ge, Yi Chen, Zhimin Lu () and Hongxia Wang ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10739-3

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