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.

Loss-of-function of KIND1, a cytoskeletal protein involved in β1-integrin function, causes Kindler Syndrome (KS), a genetic disease characterized by skin fragility, photosensitivity and increased risk of squamous cell carcinoma (SCC). Dysregulation of β1-integrin underlies KS skin fragility. However, the mechanisms underlying SCC susceptibility are unclear. Here, we demonstrate that gene silencing of KIND1 decreased keratinocyte proliferation and increased apoptosis in vitro and in skin grafts regenerated on mice, which was correlated with reduced cyclinB1. In addition, KIND1-loss sensitized keratinocytes to cytokine and UV-induced NF-κB and JNK activation and upregulation of CXCL10 and TNFα. Moreover, KIND1-loss impaired DNA-repair, as indicated by the increased detection of γH2AX and cyclobutane pyrimidine dimers (CPD) 24 hours post UVB-radiation. Genetic or pharmacological JNK-inhibition and NF-κB-inhibition markedly reduced CPD-positive cells. Further, we show that KIND1 was regulated by JunB at the transcriptional level and, like JunB, it was downregulated in human SCC cells. Together, these results indicate that KIND1 is important not only for keratinocyte proliferation but also for the suppression of UV-induced inflammation and DNA-damage. These latter findings support a tumor suppressor function for KIND1, and identified JNK and NF-κB as potential therapeutic targets for prevention of SCC in KS patients.