title: In support of fatty acid synthase (FAS) as a metabolic oncogene: extracellular acidosis acts in an epigenetic fashion activating FAS gene expression in cancer cells.
abstract: Relatively little information exists on the ultimate molecular mechanisms by which the lipogenic enzyme Fatty Acid Synthase (FAS) is differentially overexpressed in a biologically aggressive subset of human malignancies. Since the microenvironment of solid tumors contains regions of poor oxygenation and high acidity, it has recently been suggested that cancer-associated FAS is a novel metabolic oncogene conferring a selective growth advantage upon stresses such as hypoxia and/or low pH. Here, we performed transient transfection studies with a 178-bp FAS promoter fragment harboring a complex Sterol Regulatory Element Binding Proteins (SREBP)-binding site to evaluate whether extracellular low pH and/or hypoxia may act in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in cancer cells. First, MCF-7 breast cancer cells cultured in acidosis (pH 6.5), but not under hypoxia or in the presence of hypoxia mimetics, demonstrated a more than two-fold increase in the transcriptional activity of FAS promoter-reporter constructs compared with control cells grown under standard culture conditions (pH 7.4). Second, the up-regulatory effect of extracellular acidosis on the transcriptional activation of FAS gene was not observed when the FAS promoter was truncated at the SREBP-binding site. Third, MCF-7 cells engineered to overexpress the Her-2/neu (erbB-2) oncogene exhibited a SREBP-dependent activation of the FAS promoter-reporter construct up to three-fold higher than that found in wild-type MCF-7 cells, while extracellular acidosis resulted only in a marginal increase of Her-2/neu-promoted activation of FAS gene. This study reveals for the first time that extracellular acidosis can work in an epigenetic fashion by up-regulating the transcriptional expression of FAS gene in breast cancer cells, a stimulatory effect that is equally mimicked by well-characterized oncogenic stimuli such as Her-2/neu. These findings, altogether, support the "metabolic oncogene" theory for FAS overexpression in cancer cells.
authors.affiliation: Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201, USA. javiermenendez72@yahoo.com
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
authors.forename: Josiah P
authors.initials: JP
authors.lastname: Decker
authors.forename: Ruth
authors.initials: R
authors.lastname: Lupu
mesh_terms: D000138:Acidosis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009857:Oncogenes
chemical_list: D064429:Fatty Acid Synthases