Unsaturated Fatty Acids Stimulate Tumor Growth through Stabilization of β‐Catenin

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Cancer cells alter their metabolism to adapt for their uncontrolled proliferation. One of such alterations leads to accumulation of free fatty acids (FAs), which facilitate proliferation of some cancer cells through a mechanism yet to be identified. Here we report that excess unsaturated FAs block degradation of β‐catenin, the aberrant accumulation of which triggers development of various cancers. Interestingly, unsaturated FAs stabilize β‐catenin through a mechanism independent from that mediated by Wnt, a protein known to block degradation of β‐catenin. Unlike Wnt, unsaturated FAs do not affect ubiquitination of β‐catenin. Instead, the lipids block degradation of ubiquitinated β‐catenin through Fas‐associated factor 1 (FAF1), a protein known to facilitate degradation of β‐catenin through its interaction with the protein. We now show that FAF1 directly binds to unsaturated FAs. This interaction triggers polymerization of FAF1, causing dissociation of the protein from β‐catenin and consequently stabilization of β‐catenin. This finding is clinically relevant, as excess unsaturated FAs accumulated in clear cell renal cell carcinoma promote growth of the tumor through stabilization of β‐catenin. Our study indicates that overaccumulation of unsaturated FAs is a novel mechanism for cancer cells to acquire excess β‐catenin.This study is supported by grants from NIH (HL‐20948), Welch foundation (I‐1832), and Clayton Foundation for Research.