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FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms.

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Date
2016-06-07
Authors
Zhang, Xiaoling
Wu, Joseph
Luo, Suju
Lechler, Terry
Zhang, Jennifer Y
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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.
Type
Journal article
Subject
AKT
FRA1
SCC
c-Jun
cyclinB1
Permalink
https://hdl.handle.net/10161/15165
Published Version (Please cite this version)
10.18632/oncotarget.9110
Publication Info
Zhang, Xiaoling; Wu, Joseph; Luo, Suju; Lechler, Terry; & Zhang, Jennifer Y (2016). FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms. Oncotarget, 7(23). pp. 34371-34383. 10.18632/oncotarget.9110. Retrieved from https://hdl.handle.net/10161/15165.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Lechler

Terry H. Lechler

Professor in Dermatology
My lab studies how epithelial tissues of the skin and gut are formed. We are particularly interested in the roles of the cytoskeleton, cell adhesion and cell division orientations in the development and maintenance of tissues. 
Zhang

Jennifer Yunyan Zhang

Professor in Dermatology
Epidermis of the skin constitutes the largest organ and the outer most barrier of the body. It is one of the few organs that undergo lifelong self-renewal through a tight balance of cell growth, differentiation, and programmed cell death. Deregulation of this balance is manifested in many diseases, including various immune diseases and cancer.  Our lab is focused on 3 interrelated topics: 1. Gene regulation of epithelial cell proliferation and differenti
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