Downregulation of α‐ l ‐fucosidase 1 suppresses glioma progression by enhancing autophagy and inhibiting macrophage infiltration

Abstract α‐l‐Fucosidase 1 (FUCA1), a lysosomal enzyme that catalyses the hydrolytic cleavage of the terminal fucose residue, has been reported to be involved in tumorigenesis. However, the clinical significance and biological roles of FUCA1 in glioma remain largely unknown. We analyzed FUCA1 expression according to data in Oncomine, The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases and further verified FUCA1 expression with immunohistochemistry and real‐time PCR analysis in glioma tissues. The results showed that FUCA1 overexpression was significantly associated with high‐grade glioma as well as high mortality rates in the survival analysis. Data analyzed in cBioPortal showed that alterations in FUCA1 (1.4%) were correlated with worse survival in glioblastoma multiforme patients. Functional experiments showed that downregulation of FUCA1 suppressed glioma growth in vitro and in vivo. Conversely, overexpression of FUCA1 had the opposite effects on glioma. Mechanistically, transient inhibition of FUCA1 promoted the formation of large acidic vacuoles, as revealed by staining with acridine orange, increased the ratio of LC3‐B/LC3‐A, and modified the expression of Beclin‐1 and Atg12, which are autophagic markers. Upregulation of FUCA1 attenuated starvation‐induced autophagy in glioma. In addition, lower levels of tumor‐infiltrating macrophages, including CD68+ (−30%), F4/80+ (−50%), and CD11c+ macrophages (−50%), were identified in FUCA1‐downregulated glioma tissues, and CCL2/CCL5 neutralizing Abs blocked this effect. These results show that FUCA1 could serve as a potential therapeutic target for the treatment of patients with glioma by enhancing autophagy and inhibiting macrophage infiltration.