Arylsulfatase D promotes malignant phenotypes in glioblastoma cells and is linked to altered Hippo pathway phosphorylation

Abstract

Introduction Glioblastoma (GBM) is a highly aggressive malignant brain tumor with persistently poor clinical outcomes and few effective treatment options. Arylsulfatase D (ARSD), a lysosomal sulfatase implicated in several cancers, has not been fully characterized in GBM. Methods ARSD expression in GBM was evaluated using bioinformatic analyses and immunohistochemical validation. ARSD was overexpressed or knocked down in U87MG, U251MG, and A172 cells, and proliferation, three-dimensional spheroid growth, apoptosis, invasion, and Matrigel-based tube-like network formation were assessed. Merlin/LATS/YAP phosphorylation-related protein patterns were analyzed. Irosustat was further evaluated in a subcutaneous U87MG xenograft model. Results ARSD was upregulated in GBM tissues, and higher ARSD expression was associated with unfavorable patient survival. ARSD overexpression enhanced proliferation, three-dimensional spheroid growth, invasion, and Matrigel-based tube-like network formation while reducing apoptosis, whereas ARSD knockdown suppressed these malignant phenotypes. ARSD expression was associated with altered Merlin/LATS/YAP phosphorylation-related protein patterns, particularly changes in YAP1 abundance and phosphorylation status. In the xenograft model, Irosustat treatment altered YAP phosphorylation-associated protein patterns, enhanced tumor cell apoptosis, reduced tumor burden, and prolonged mouse survival. Discussion These findings indicate that ARSD facilitates GBM malignant behavior and is linked to Merlin/LATS/YAP phosphorylation-related signaling. Irosustat showed preliminary antitumor activity in the xenograft model; however, because Irosustat is not an ARSD-specific inhibitor, the in vivo findings should not be interpreted as evidence of selective ARSD inhibition.