FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms.
FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms.
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DOI：
10.18632/oncotarget.9110
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发表时间：
2016-06-07
期刊：
影响因子：
--
通讯作者：
Zhang JY
中科院分区：
文献类型：
--
作者：
Zhang X;Wu J;Luo S;Lechler T;Zhang JY
FRA1（类Fos抗原1）在许多上皮癌中高度表达，包括皮肤鳞状细胞癌（cSCC）和头颈部鳞状细胞癌（HNSCC）。然而，在这些癌症中FRA1功能的重要性以及介导其功能的机制尚未完全明确。在此，我们证明在HNSCC和cSCC细胞中FRA1基因沉默导致两种结果——细胞增殖和迁移受损。FRA1对细胞生长的调控不同于c - Jun，c - Jun是Jun家族中一个重要的AP - 1因子。虽然c - Jun是G1/S期细胞周期启动子CDK4表达所必需的，但FRA1对AKT激活以及细胞周期蛋白B1（一种G2 - M期进展所必需的分子）的AKT依赖性表达至关重要。外源性表达组成型激活形式的AKT可挽救因FRA1缺失导致的癌细胞生长缺陷。此外，FRA1敲低显著减缓细胞黏附和迁移，相反，活性FRA1突变体（FRA1DD）的表达以JNK/c - Jun依赖的方式加速这些过程。通过蛋白质和染色质免疫沉淀 - 聚合酶链反应（ChIP - PCR）分析，我们确定KIND1（一种细胞黏附分子β1 - 整合素的细胞骨架调节因子）是一个新的FRA1转录靶点。恢复KIND1的表达可挽救因FRA1缺失诱导的迁移缺陷。与这些体外数据一致，FRA1缺失的HNSCC细胞皮下肿瘤生长和肺转移速率显著降低。总之，这些结果表明FRA1通过AKT促进癌症生长，并通过JNK/c - Jun增强癌细胞迁移，确定FRA1是JNK和AKT信号通路的关键整合因子，是cSCC和HNSCC的一个潜在治疗靶点。
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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