title: AURKA Overexpression Is Driven by FOXM1 and MAPK/ERK Activation in Melanoma Cells Harboring BRAF or NRAS Mutations: Impact on Melanoma Prognosis and Therapy.
abstract: The cell cycle-related genes AURKA and FOXM1 are overexpressed in melanoma. We show here that AURKA overexpression is associated with poor prognosis in three independent cohorts of melanoma patients and correlates with the presence of genomic amplification of AURKA locus and BRAFV600Emutation. AURKA overexpression may also be driven by increased promoter activation through elements such as ETS and FOXM1 found within the 5' proximal promoter region. Activated MAPK/ERK signaling pathway mediates robust AURKA promoter activation, thereby knockdown of BRAFV600Eand ERK inhibition results in reduced AURKA transcription and expression. We show a positive correlation between FOXM1 and AURKA expression in three independent cohorts of melanoma patients. FOXM1 silencing decreases expression of AURKA and late cell cycle genes in melanoma cells. We further found that FOXM1 expression levels are significantly higher in tumors carrying the BRAFV600Emutation compared with the wild-type BRAF (BRAFwt). Accordingly, the knockdown of BRAFV600Ealso reduces the expression of FOXM1 in BRAFV600Ecells. Moreover, Aurora kinase A and FOXM1 inhibition by either genetic knockdown or pharmacologic inhibitors impair melanoma growth and survival both in culture and in vivo, underscoring their therapeutic value for melanoma patients who fail to benefit from BRAF/MEK signaling inhibition.
authors.affiliation: Biochemistry and Molecular Genetics Service, Melanoma Unit, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Joan Anton
authors.initials: JA
authors.lastname: Puig-Butille
authors.affiliation: IDIBELL (Bellvitge Biomedical Research Institute), Centre d' Oncologia Molecular, Barcelona, Spain.
authors.forename: Antònia
authors.initials: A
authors.lastname: Vinyals
authors.affiliation: Dermatology Service, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Josep R
authors.initials: JR
authors.lastname: Ferreres
authors.affiliation: Dermatology Department, Melanoma Unit, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Aguilera
authors.affiliation: IDIBELL (Bellvitge Biomedical Research Institute), Centre d' Oncologia Molecular, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Cabré
authors.affiliation: Dermatology Department, Melanoma Unit, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Tell-Martí
authors.affiliation: Dermatology Service, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Marcoval
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), IDIBELL, Barcelona, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mateo
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), IDIBELL, Barcelona, Spain.
authors.forename: Luís
authors.initials: L
authors.lastname: Palomero
authors.affiliation: Biochemistry and Molecular Genetics Service, Melanoma Unit, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Badenas
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), IDIBELL, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Piulats
authors.affiliation: Dermatology Department, Melanoma Unit, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Malvehy
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), IDIBELL, Barcelona, Spain.
authors.forename: Miquel A
authors.initials: MA
authors.lastname: Pujana
authors.affiliation: Dermatology Department, Melanoma Unit, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Puig
authors.affiliation: IDIBELL (Bellvitge Biomedical Research Institute), Centre d' Oncologia Molecular, Barcelona, Spain. Electronic address: afabra@idibell.cat.
authors.forename: Àngels
authors.initials: À
authors.lastname: Fabra
mesh_terms: D000818:Animals; D001226:Aspartate-tRNA Ligase / Q000235:genetics*; D064096:Aurora Kinase A / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D000072278:Forkhead Box Protein M1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics*; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D012346:RNA, Transfer, Amino Acyl; C576917:AURKA protein, human; D064096:Aurora Kinase A; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D001226:Aspartate-tRNA Ligase; C029194:asparaginyl-tRNA synthetase