JOURNAL ARTICLE

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

Javier A Menendez, Josiah P Decker, Ruth Lupu
Journal of Cellular Biochemistry 2005 January 1, 94 (1): 1-4
15523670
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
15523670
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"