Zhenfeng Wang 1, Shunshun Li 2 3, Xu Sun 1, Dianheng Wang 1, Yabo Zhou 1, Li Zhou 1, Jie Chen 1, NanNan Zhou 1, Qiuying Zhu 4, Jinyan Liu 5, Guihong Zhang 6, Wei-Min Tong 7, Jiadi Lv 1, Bo Huang 1

Protein Cell. 2025 Nov 19:pwaf100.

PMID: 41259014 DOI: 10.1093/procel/pwaf100

Abstract

Sonic hedgehog subgroup medulloblastoma (SHH-MB), an aggressive pediatric brain tumor that originates from granule neuron precursors, faces the challenge of poor treatment owing to its unclear molecular mechanisms. Here, we show that sialic acid-binding immunoglobulin-like receptor 15 (Siglec-15), an immunosuppressive membrane protein, is upregulated and mediates SHH-MB growth through its translocation to the lysosomal membrane. We found that SHH-MB cells use the cation-independent mannose 6-phosphate receptor (CI-MPR) to transport Siglec-15 from the trans-Golgi network (TGN) to lysosomes, where Siglec-15 induces lysosomal Ca2+ release by interacting with mucolipin TRP cation channel 1 (TRPML1), leading to the nuclear translocation of the transcription factor EB (TFEB). Blockade of Siglec-15, TRPML1 or TFEB hinders SHH-MB growth in vitro and in vivo. Importantly, aryl hydrocarbon receptor (AhR), a cytoplasmic transcription factor, upregulates Siglec-15 expression. AhR inhibition by CH-223191 or StemRegenin 1 (SR1) achieved therapeutic efficacy against orthotopic SHH-MB xenografts in mice. These findings reveal an essential role for the AhR-siglec-15 axis in SHH-MB development, providing a potential strategy for SHH-MB treatment.

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