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.

癌症干细胞（CSC）代表了治疗耐药性和肿瘤进展的主要来源。但是，对CSCs干性的调控尚不完全清楚。在这里，我们报告TSPAN8表达在乳腺CSCs中上调，促进干基因NANOG，OCT4和ALDHA1的表达，并与治疗耐药性相关。从机理上讲，TSPAN8与PTCH1相互作用并通过募集去泛素化酶ATXN3抑制SHH / PTCH1复合物的降解。这导致SMO易位至纤毛，下游基因表达，CSC对化学治疗剂的抗性并增强了小鼠的肿瘤形成。因此，在人类乳腺癌标本中，TSPAN8，PTCH1，SHH和ATXN3的表达水平呈正相关，TSPAN8和ATXN3的高表达水平与不良预后相关。这些发现揭示了TSPAN8增强的Sonic Hedgehog信号传导的分子基础，并突显了TSPAN8在促进癌症干中的作用。