Some cancer cells exhibit elevated levels of free fatty acids (FAs) as well as high levels of β-catenin, a transcriptional co-activator that promotes their growth. Here, we link these two phenomena by showing that unsaturated FAs inhibit degradation of β-catenin. Unsaturated FAs bind to the UAS domain of Fas-associated factor 1 (FAF1), a protein known to bind β-catenin, accelerating its degradation. FA binding disrupts the FAF1/β-catenin complex, preventing proteasomal degradation of ubiquitinated β-catenin. This mechanism for stabilization of β-catenin differs from that of Wnt signaling, which blocks ubiquitination of β-catenin. In clear cell renal cell carcinoma (ccRCC) cells, unsaturated FAs stimulated cell proliferation through stabilization of β-catenin. In tissues from biopsies of human ccRCC, elevated levels of unsaturated FAs correlated with increased levels of β-catenin. Thus, targeting FAF1 may be an effective approach to treat cancers that exhibit elevated FAs and β-catenin.
