title: FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms.
abstract: FRA1 (Fos-like antigen 1) is highly expressed in many epithelial cancers including squamous cell carcinoma of the skin (cSCC) and head and neck (HNSCC). However, the functional importance and the mechanisms mediating FRA1 function in these cancers are not fully understood. Here, we demonstrate that FRA1 gene silencing in HNSCC and cSCC cells resulted in two consequences - impaired cell proliferation and migration. FRA1 regulation of cell growth was distinct from that of c-Jun, a prominent Jun group AP-1 factor. While c-Jun was required for the expression of the G1/S phase cell cycle promoter CDK4, FRA1 was essential for AKT activation and AKT-dependent expression of CyclinB1, a molecule required for G2-M progression. Exogenous expression of a constitutively active form of AKT rescued cancer cell growth defect caused by FRA1-loss. Additionally, FRA1 knockdown markedly slowed cell adhesion and migration, and conversely expression of an active FRA1 mutant (FRA1DD) expedited these processes in a JNK/c-Jun-dependent manner. Through protein and ChIP-PCR analyses, we identified KIND1, a cytoskeletal regulator of the cell adhesion molecule β1-integrin, as a novel FRA1 transcriptional target. Restoring KIND1 expression rescued migratory defects induced by FRA1 loss. In agreement with these in vitro data, HNSCC cells with FRA1 loss displayed markedly reduced rates of subcutaneous tumor growth and pulmonary metastasis. Together, these results indicate that FRA1 promotes cancer growth through AKT, and enhances cancer cell migration through JNK/c-Jun, pinpointing FRA1 as a key integrator of JNK and AKT signaling pathways and a potential therapeutic target for cSCC and HNSCC.
authors.affiliation: Department of Dermatology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Dermatology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Suju
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Dermatology, Duke University School of Medicine, Durham, NC, USA.|Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Lechler
authors.affiliation: Department of Dermatology, Duke University School of Medicine, Durham, NC, USA.|Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D056744:Cyclin B1 / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D004789:Enzyme Activation / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms / Q000473:pathology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D000099169:Fos-Related Antigen 1
chemical_list: D056744:Cyclin B1; D051358:Cyclin-Dependent Kinase 4; D019012:Integrin beta1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D000099169:Fos-Related Antigen 1; C534699:CCNB1 protein, human; C475301:FERMT1 protein, human; C495900:CDK4 protein, human
keywords: AKT; FRA1; SCC; c-Jun; cyclinB1