title: Unsaturated Fatty Acids Stimulate Tumor Growth through Stabilization of β-Catenin.
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.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Hyeonwoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Navas
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Rahul K
authors.initials: RK
authors.lastname: Kollipara
authors.affiliation: Kidney Cancer Program in Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Pedrosa
authors.affiliation: Kidney Cancer Program in Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kittler
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jin.ye@utsouthwestern.edu.
authors.forename: Jin
authors.initials: J
authors.lastname: Ye
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016466:CHO Cells; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D054875:Ubiquitination; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C490780:FAF1 protein, human; D005231:Fatty Acids, Unsaturated; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex