SASH1 Modulates Melanin Synthesis and Melanoma Cell Metastasis via Suppression of the TGF ‐β Signaling Pathway

Dyschromatosis universalis hereditaria (DUH) is characterized by autosomal dominant inheritance and widespread involvement of hyperpigmentation and depigmentation. In our previous study, we identified mutations in the SH3 domain-containing protein 1 (SASH1) associated with the DUH phenotype in Chinese families and predicted that the SASH1/THBS1/TGF-β1 signaling pathway mediates melanin production and melanocyte transport. However, the molecular regulatory mechanisms remain unclear. By modulating the expression of SASH1 and THBS1, we assessed the expression of genes within the SASH1/THBS1/TGF-β1 pathway and evaluated cell phenotypes and melanin synthesis in the A375 and PIG1 cell lines. Through in vivo subcutaneous injection of SASH1 knockdown A375 cells into nude mice, we tested whether SASH1-TGF-β1 signaling may regulate cancer growth. Our findings demonstrated that SASH1 inhibits proliferation, migration, invasion, epithelial-mesenchymal transition, and promotes melanin synthesis through TGF-β1 signaling, while THBS1 counteracts the increase in TGF-β1 levels induced by SASH1 knockdown. We further showed that SASH1 suppresses TGF-β1 through its regulatory effect on THBS1, thereby inhibiting melanin metastasis and promoting melanin synthesis, which offers potential therapeutic insights into the modulation of TGF-β1.