Novel p53 target gene FUCA1 encodes a fucosidase and regulates growth and survival of cancer cells

Abstract

The tumor suppressor p53 functions by inducing the transcription of a collection of target genes. We previously attempted to identify p53 target genes by microarray expression and ChIP‐sequencing analyses. In this study, we describe a novel p53 target gene, FUCA1, which encodes a fucosidase. Although fucosidase, α‐l‐1 (FUCA1) has been reported to be a lysosomal protein, we detected it outside of lysosomes and observed that its activity is highest at physiological pH. As there is a reported association between fucosylation and tumorigenesis, we investigated the potential role of FUCA1 in cancer. We found that overexpression of FUCA1, but not a mutant defective in enzyme activity, suppressed the growth of cancer cells and induced cell death. Furthermore, we showed that FUCA1 reduced fucosylation and activation of epidermal growth factor receptor, and concomitantly suppressed epidermal growth factor signaling pathways. FUCA1 loss‐of‐function mutations are found in several cancers, its expression is reduced in cancers of the large intestine, and low FUCA1 expression is associated with poorer prognosis in several cancers. These results show that protein defucosylation mediated by FUCA1 is involved in tumor suppression.

Alpha‐L‐fucosidase‐1 is a diagnostic marker that distinguishes mucoepidermoid carcinoma from squamous cell carcinoma

“…FUCA1 is induced by wild‐type p53 according to in vitro studies, and the expression of FUCA1 is downregulated in cancers with mutant p53 . Because that particular mutant p53 has an extended protein half‐life, an intensified signal can be detected at high frequency in OSCC and severe dysplasia .…”

“…Recently, Ezawa et al . reported that FUCA1 was induced by wild‐type p53 . Many OSCC cases have mutations in TP53 , and strong chromogenic reaction to p53 caused by an increased half‐life of mutant p53 is detected in OSCC at high frequency .…”

Plasma α‐L‐fucosidase‐1 in patients with Sjögren's syndrome and other rheumatic disorders

“…Based on data from previous works, it seems that no previous evidence about a relationship between α‐L‐FUCA‐1 and SS have yet been described. While genetic expression of α‐L‐FUCA‐1 has been recently correlated with tumors which suggests an important role of this glycosidase in chronic inflammatory response, fucosidase activity is closely related to lysosomal function, and its importance in the onset and progression of inflammation and autoimmune diseases has earlier been reviewed …”

“…Based on data from previous works, it seems that no previous evidence about a relationship between α-L-FUCA-1 and SS have yet been described. While genetic expression of α-L-FUCA-1 has been recently correlated with tumors 27,28 which suggests an important role of this glycosidase in chronic inflammatory response, fucosidase activity is closely related to lysosomal function, and its importance in the onset and progression of inflammation and autoimmune diseases has earlier been reviewed. 29 Interestingly, in SS the chronic inflammatory state is exacerbated by lysosome function, which in animal models has been shown to Statistics were calculated in a triplicate experiment with a minimal size of 10-20 samples, according to methods described in the text.…”

First characterization of fucosidases in spiders

“…However, only a few fucosidases from distinct eukaryotes have been described despite the ubiquity of fucosidases in Metazoa (Intra, Perotti, Pavesi, & Horner, 2007) and the involvement of -L-fucosidases in many physiological processes (Ezawa et al, 2016;Goi et al, 1986Goi et al, , 1999.…”