title: Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway.
abstract: Usp5 is a deubiquitinase (DUB) previously shown to regulate unanchored poly-ubiquitin (Ub) chains, p53 transcriptional activity and double-strand DNA repair. In BRAF mutant melanoma cells, Usp5 activity was suppressed by BRAF inhibitor (vemurafenib) in sensitive but not in acquired or intrinsically resistant cells. Usp5 knockdown overcame acquired vemurafenib resistance and sensitized BRAF and NRAS mutant melanoma cells to apoptosis initiated by MEK inhibitor, cytokines or DNA-damaging agents. Knockdown and overexpression studies demonstrated that Usp5 regulates p53 (and p73) levels and alters cell growth and cell cycle distribution associated with p21 induction. Usp5 also regulates the intrinsic apoptotic pathway by modulating p53-dependent FAS expression. A small molecule DUB inhibitor (EOAI3402143) phenocopied the FAS induction and apoptotic sensitization of Usp5 knockdown and fully blocked melanoma tumor growth in mice. Overall, our results demonstrate that BRAF activates Usp5 to suppress cell cycle checkpoint control and apoptosis by blocking p53 and FAS induction; all of which can be restored by small molecule-mediated Usp5 inhibition. These results suggest that Usp5 inhibition can provide an alternate approach in recovery of diminished p53 (or p73) function in melanoma and can add to the targeted therapies already used in the treatment of melanoma.
authors: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
authors: Harish
authors: H
authors: Potu
authors: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
authors: Luke F
authors: LF
authors: Peterson
authors: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
authors: Anupama
authors: A
authors: Pal
authors: Department of Dermatology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
authors: Monique
authors: M
authors: Verhaegen
authors: Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts.
authors: Juxiang
authors: J
authors: Cao
authors: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
authors: Moshe
authors: M
authors: Talpaz
authors: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
authors: Nicholas J
authors: NJ
authors: Donato
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000097:blood*
chemical_list: D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D010450:Endopeptidases; C091939:ubiquitin isopeptidase