AURKA Overexpression Is Driven by FOXM1 and MAPK/ERK Activation in Melanoma Cells Harboring BRAF or NRAS Mutations: Impact on Melanoma Prognosis and Therapy
AURKA Overexpression Is Driven by FOXM1 and MAPK/ERK Activation in Melanoma Cells Harboring BRAF or NRAS Mutations: Impact on Melanoma Prognosis and Therapy
复制标题
DOI：
10.1016/j.jid.2017.01.021
复制
发表时间：
2017-06-01
影响因子：
6.5
通讯作者：
Fabra, Angels
中科院分区：
文献类型：
--
作者：
Anton Puig-Butille, Joan;Vinyals, Antonia;Fabra, Angels
细胞周期相关基因AURKA和FOXM1在黑色素瘤中过度表达。我们在这里表明，在三个独立的黑色素瘤患者队列中，AURKA的过度表达与不良预后相关，并与AURKA基因座和BRAF(V600E)突变的存在相关。AURKA的过度表达也可能是由于启动子激活增加，在50近端的启动子区域发现了Ets和FOXM1等元件。激活的MAPK/ERK信号通路介导了强大的AURKA启动子激活，从而抑制BRAF(V600E)和ERK导致AURKA转录和表达减少。我们发现FOXM1和AURKA在三个独立的黑色素瘤患者队列中的表达呈正相关。FOXM1沉默降低黑色素瘤细胞AURKA和细胞周期晚期基因的表达。我们进一步发现，在携带BRAF(V600E)突变的肿瘤中，FOXM1的表达水平显著高于野生型BRAF(BRAF Wt)。相应地，BRAF(V600E)基因的敲除也降低了FOXM1在BRAF(V600E)细胞中的表达。此外，通过基因敲除或药物抑制剂抑制Aurora Kinase A和FOXM1会损害黑色素瘤的生长和存活，这突显了它们对未能从BRAF/MEK信号抑制中受益的黑色素瘤患者的治疗价值。
The cell cycle-related genes AURKA and FOXM1 are overexpressed in melanoma. We show here that AURKA overexpression is associated with poor prognosis in three independent cohorts of melanoma patients and correlates with the presence of genomic amplification of AURKA locus and BRAF(V600E) mutation. AURKA overexpression may also be driven by increased promoter activation through elements such as ETS and FOXM1 found within the 50 proximal promoter region. Activated MAPK/ERK signaling pathway mediates robust AURKA promoter activation, thereby knockdown of BRAF(V600E) and ERK inhibition results in reduced AURKA transcription and expression. We show a positive correlation between FOXM1 and AURKA expression in three independent cohorts of melanoma patients. FOXM1 silencing decreases expression of AURKA and late cell cycle genes in melanoma cells. We further found that FOXM1 expression levels are significantly higher in tumors carrying the BRAF(V600E) mutation compared with the wild-type BRAF ( BRAF wt). Accordingly, the knockdown of BRAF(V600E) also reduces the expression of FOXM1 in BRAF(V600E) cells. Moreover, Aurora kinase A and FOXM1 inhibition by either genetic knockdown or pharmacologic inhibitors impair melanoma growth and survival both in culture and in vivo, underscoring their therapeutic value for melanoma patients who fail to benefit from BRAF/MEK signaling inhibition.