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.