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.
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https://hdl.handle.net/10161/15165Published Version (Please cite this version)
10.18632/oncotarget.9110Publication 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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Terry H. Lechler
Professor in Dermatology
My lab is interested in understanding how tissue architecture and physiology are controlled.
We study this in a variety of organ systems, including the skin the gut, and with
approaches ranging from in vitro reconstitution to in vivo mouse models. Our goal
is to understand the underlying cell biology controlling tissue development and function.
We are particularly interested in the roles of cell-cell interactions, adhesion and
the cytoskeleton in the control of stem cell fate and differentiation
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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