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.
[1]Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Oncol, Shanghai 200080, Peoples R China.
[2]Ludwig Maximilians Univ Munchen, Dept Otorhinolaryngol Head & Neck Surg, Grosshadern Med Ctr, Munich, Germany.
[3]Liyang Peoples Hosp, Liyang 213300, Jiangsu, Peoples R China.
[4]Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Breast Thyroid Vasc Surg, Shanghai 201620, Peoples R China.
[5]Shanghai Univ Med & Hlth Sci, Shanghai Key Lab Mol Imaging, Shanghai 201318, Peoples R China.
[6]Dalian Univ Technol, Sch Pharmaceut Sci & Technol, Dalian 116024, Peoples R China.
[7]Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China.
[8]Zhejiang Univ, Sch Med, Affiliated Hosp 1, Zhejiang Prov Key Lab Pancreat Dis, Hangzhou 310029, Zhejiang, Peoples R China.
[9]Zhejiang Univ, Sch Med, Inst Translat Med, Hangzhou 310029, Zhejiang, Peoples R China.
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