TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling

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

doi:10.1038/s41467-019-10739-3

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.

Highlights

Cancer stem cells (CSCs) represent a major source of treatment resistance and tumor progression
We showed that expression of NANOG and OCT4, which are transcription factors involved in the maintenance of the pluripotent state of stem cells[23,24], was enhanced in the TS+ cells (Fig. 1e)
We demonstrated here that TSPAN8 overexpression promoted the expression of stem cell markers, like ALDHA1, increased the CD44+/CD24− cell ratio, and enhanced the expression of pluripotency transcription factors including SOX2, OCT4, and NANOG

Summary

Introduction

Cancer stem cells (CSCs) represent a major source of treatment resistance and tumor progression. 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. 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. The binding of ligand relieves the suppression of Smoothened (Smo) through PKA-, CK1α-, or G-protein-coupled receptor kinase-2 (Grk2)-mediated phosphorylation of Smo, triggering an interaction of Smo with Kif3a and β-arrestin (Arrb2), and subsequent ciliary localization of Smo[12] These series of processes facilitate the release of full-length transcriptionally active Gli proteins (GliA) from the suppressor of fused (Sufu). Stabilized SHH/PTCH1 promotes the binding of GRK2 protein kinase to SMO and the subsequent SMO phosphorylation, translocation of SMO to cilia, and GLI1 activation for downstream gene expression

Methods

Results

Conclusion