Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of β-catenin in prostate cancer

Abstract

Fatty acid synthase (FASN), a key metabolic enzyme for liponeogenesis highly expressed in several human cancers, displays oncogenic properties such as resistance to apoptosis and induction of proliferation when overexpressed. To date, no mechanism has been identified to explain the oncogenicity of FASN in prostate cancer. We generated immortalized prostate epithelial cells (iPrEC) overexpressing FASN, and found that 14C-acetate incorporation into palmitate synthesized de novo by FASN was significantly elevated in immunoprecipitated Wnt-1 when compared to isogenic cells not overexpressing FASN. Overexpression of FASN caused membranous and cytoplasmic β-catenin protein accumulation and activation, while FASN knockdown by short hairpin RNA (shRNA) resulted in a reduction in the extent of β-catenin activation. Orthotopic transplantation of iPrEC cells overexpressing FASN in nude mice resulted in invasive tumors that overexpressed β-catenin. A strong significant association between FASN and cytoplasmic (stabilized) β-catenin immunostaining was found in 862 cases of human prostate cancer after computerized subtraction of the membranous β-catenin signal (P<0.001, Spearman’s rho=0.33). We propose that cytoplasmic stabilization of β-catenin through palmitoylation of Wnt-1 and subsequent activation of the pathway is a potential mechanism of FASN oncogenicity in prostate cancer.

De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy

“…As described above, FASN and tumour-related survival signals are mutually regulated, and FASN controls HER2-dependent signalling. Besides the role of FASN-dependent fatty-acid synthesis in fatty-acid supply for membrane production and energy production through b-oxidation, FASN overexpression is further associated with palmitoylation of signalling proteins (Fiorentino et al, 2008). Interference of these pathways could also be involved in the FASN inhibition-induced selective cancer cytotoxicity.…”

Involvement of de novo synthesized palmitate and mitochondrial EGFR in EGF induced mitochondrial fusion of cancer cells

“…16 Overexpression of FASN increases the oncogenic activity of ErbB members. 17 We hypothesized that EGF induced de novo synthesized palimitate may activate mtEGFR.…”

“…15 Elevated de novo palmitate synthesis is associated with palmitoylation of Wnt1 and activation of Wnt1/β-catenin pathway. 16 Accumulating evidence indicates that FASN activity is closely associated with the survival functions of receptor tyrosine kinases of the EGFR family, which include EGFR/HER1, HER2, HER3, and HER4. Overexpression of FASN activates EGFR and HER2 signaling in breast epithelial cells.…”

Chemoresistance in Cancer Stem Cells and Strategies to Overcome Resistance

“…Resveratrol inhibits fatty acid synthase (FASN) in breast cancer cell-line-derived CSCs, thus suppressing their proliferation [92]. Overexpression of FASN has been associated with increased stability of β-catenin [93] thus, inhibition of FASN likely results in decreased Wnt signaling. More recent findings suggest that resveratrol may be able to inhibit CSC migration and invasion in pancreatic cancer [94].…”