title: Aberrant Phosphorylation of SMAD4 Thr277-Mediated USP9x-SMAD4 Interaction by Free Fatty Acids Promotes Breast Cancer Metastasis.
abstract: Obesity increases the risk of distant metastatic recurrence and reduces breast cancer survival. However, the mechanisms behind this pathology and identification of relevant therapeutic targets are poorly defined. Plasma free fatty acids (FFA) levels are elevated in obese individuals. Here we report that TGFβ transiently activates ERK and subsequently phosphorylates SMAD4 at Thr277, which facilitates a SMAD4-USP9x interaction, SMAD4 nuclear retention, and stimulates TGFβ/SMAD3-mediated transcription of Twist and Snail. USP9x inhibited the E3 ubiquitin-protein ligase TIF1γ from binding and monoubiquitinating SMAD4, hence maintaining the SMAD4 nuclear retention. FFA further facilitated TGFβ-induced ERK activation, SMAD4 phosphorylation, and nuclear retention, promoting TGFβ-dependent cancer progression. Inhibition of ERK and USP9x suppressed obesity-induced metastasis. In addition, clinical data indicated that phospho-ERK and -SMAD4 levels correlate with activated TGFβ signaling and metastasis in overweight/obese patient breast cancer specimens. Altogether, we demonstrate the vital interaction of USP9x and SMAD4 for governing TGFβ signaling and dyslipidemia-induced aberrant TGFβ activation during breast cancer metastasis.Cancer Res; 77(6); 1383-94. ©2017 AACR.
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California. yongwu@cdrewu.edu jayvadgama@cdrewu.edu.|David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Yi
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California.|Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Sami
authors.initials: S
authors.lastname: Dwabe
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Atefi
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Yahya
authors.initials: Y
authors.lastname: Elshimali
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Kemp
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Kruttika
authors.initials: K
authors.lastname: Bhat
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Jesse
authors.initials: J
authors.lastname: Haro
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sarkissyan
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California. yongwu@cdrewu.edu jayvadgama@cdrewu.edu.|David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California.
authors.forename: Jaydutt V
authors.initials: JV
authors.lastname: Vadgama
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009765:Obesity / Q000503:physiopathology; D010766:Phosphorylation; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D014408:Biomarkers, Tumor; D005230:Fatty Acids, Nonesterified; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C506234:USP9X protein, human; D043222:Ubiquitin Thiolesterase