Abstract

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. Kim et al. demonstrate that excess unsaturated fatty acids produced in cancer cells stabilize β-catenin. This mechanism, which is independent of Wnt-mediated stabilization of β-catenin, requires direct interaction of the fatty acids with FAF1, a protein facilitating degradation of β-catenin. This interaction inactivates FAF1, thereby stabilizing β-catenin.

Original languageEnglish (US)
Article number2062
Pages (from-to)495-503
Number of pages9
JournalCell Reports
Volume13
Issue number3
DOIs
StatePublished - Oct 20 2015

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Catenins
Unsaturated Fatty Acids
Tumors
Stabilization
Growth
Neoplasms
Degradation
Fatty Acids
Cells
Renal Cell Carcinoma
Biopsy
Ubiquitination
Cell proliferation
Nonesterified Fatty Acids
Proteolysis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Unsaturated Fatty Acids Stimulate Tumor Growth through Stabilization of β-Catenin. / Kim, Hyeonwoo; Rodriguez-Navas, Carlos; Kollipara, Rahul K.; Kapur, Payal; Pedrosa, Ivan; Brugarolas, James; Kittler, Ralf; Ye, Jin.

In: Cell Reports, Vol. 13, No. 3, 2062, 20.10.2015, p. 495-503.

Research output: Contribution to journalArticle

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