期刊
CARCINOGENESIS
卷 41, 期 9, 页码 1246-1252出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgaa053
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资金
- Ministero della Salute, fondo 5x1000 Enti della Ricerca Sanitaria 2014
- Ministero della Salute, fondo 5x1000 Enti della Ricerca Sanitaria 2015
- Ministero della Salute, fondo 5x1000 Enti della Ricerca Sanitaria 2016
Castration-resistant prostate cancer (CRPC) is an incurable stage of the disease. A multivariate principal component analysis on CRPC in vitro models identified aspartyl (asparaginyl) beta hydrolase (ASPH) as the most relevant molecule associated with the CRPC phenotype. ASPH is overexpressed in various malignant neoplasms and catalyzes the hydroxylation of aspartyl and asparaginyl residues in the epidermal growth factor (EGF)-like domains of proteins like NOTCH receptors and ligands, enhancing cell motility, invasion and metastatic spread. Bioinformatics analyses of ASPH in prostate cancer (PCa) and CRPC datasets indicate that ASPH gene alterations have prognostic value both in PCa and CRPC patients. In CRPC cells, inhibition of ASPH expression obtained through specific small interfering RNA or culturing cells in hypoxic conditions, reduced cell proliferation, invasion and cyclin D1 expression through modulation of the NOTCH signaling. ASPH and HIF1 alpha crosstalk, within a hydroxylation-regulated signaling pathway, might be transiently driven by the oxidative stress evidenced inside CRPC cells. In addition, increased phosphorylation of GSK3 beta by ASPH silencing demonstrates that ASPH regulates GSK3 beta activity inhibiting its interactions with upstream kinases. These findings demonstrate the critical involvement of ASPH in CRPC development and may represent an attractive molecular target for therapy.
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