1. ¹Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA
2. ²Department of Urology, the Children's Hospital, Harvard Medical School, Boston, MA, USA
3. ³The Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA
4. ⁴Department of Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA
5. ⁵Channing Laboratory, Department of Epidemiology, Brigham and Women's Hospital, Harvard School of Public Health, Boston, MA, USA

Correspondence: Professor M Loda, MD, Dana-Farber Cancer Institute, D1536, 44 Binney Street, Boston, MA 02115, USA. E-mail: massimo_loda@dfci.harvard.edu

⁶These authors equally contributed to this paper.

Received 30 May 2008; Revised 20 August 2008; Accepted 21 August 2008; Published online 6 October 2008.

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 (iPrECs) 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 -catenin protein accumulation and activation, whereas FASN knockdown by short-hairpin RNA resulted in a reduction in the extent of -catenin activation. Orthotopic transplantation of iPrECs overexpressing FASN in nude mice resulted in invasive tumors that overexpressed -catenin. A strong significant association between FASN and cytoplasmic (stabilized) -catenin immunostaining was found in 862 cases of human prostate cancer after computerized subtraction of the membranous -catenin signal (P<0.001, Spearman's =0.33). We propose that cytoplasmic stabilization of -catenin through palmitoylation of Wnt-1 and subsequent activation of the pathway is a potential mechanism of FASN oncogenicity in prostate cancer.