KAP1 inhibits the Raf-MEK-ERK pathway to promote tumorigenesis in A549 lung cancer cells
KAP1 inhibits the Raf-MEK-ERK pathway to promote tumorigenesis in A549 lung cancer cells
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KAP1抑制Raf-MEK-ERK通路促进A549肺癌细胞肿瘤发生
DOI：
10.1002/mc.22853
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发表时间：
2018-10-01
影响因子：
4.6
通讯作者：
Xu, Tian-Rui
中科院分区：
文献类型：
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作者：
Wu, Guo-Jin;Pen, Jun;Xu, Tian-Rui
Raf-MEK-ERK通路的异常激活经常与多种癌症，特别是肺癌有关。然而，这一途径的关键调控因子在很大程度上是未知的。通过功能蛋白质组学筛选，我们发现KAP1与c-Raf相互作用。KAP1基因敲除后，丝氨酸259位的c-Raf磷酸化水平降低，而丝氨酸338位的c-Raf磷酸化水平升高，从而激活了MEK和ERK。我们检测到KAP1在肺癌组织中的表达高于正常癌旁组织。KAP1基因敲除使A549肺癌细胞停滞在细胞周期的G0/G1期，并抑制细胞生长、转移、上皮-间充质转化、血管生成、干化和集落形成。此外，敲除KAP1显著增加了A549细胞对抗癌药物5-氟尿嘧啶的敏感性，这与ERK磷酸化增加有关。体内移植实验表明，KAP1缺乏可显著降低A549细胞的致瘤性。综上所述，我们的研究结果表明，KAP1在c-Raf-相互作用组复合体中扮演关键模块的角色，并通过Raf-MEK-ERK途径调节肺癌的发展。因此，KAP1可能是一种潜在的肺癌诊断生物标志物和新的治疗靶点。
Aberrant activation of the Raf-MEK-ERK pathway has frequently been associated with various cancers, especially lung cancer. However, the key regulators of this pathway are largely unknown. Using functional proteomics screening, we found that KAP1 interacts with c-Raf. Knocking out KAP1 decreased c-Raf phosphorylation at serine 259 and increased its phosphorylation at serine 338, which activated MEK and ERK. We detected higher KAP1 expression in lung cancer tissues than in normal peri-tumoral tissues. KAP1 knockdown arrested A549 lung cancer cells in the G0/G1 phase of the cell cycle and attenuated cell growth, metastasis, the epithelial-mesenchymal transition, angiogenesis, stemness, and colony formation. Furthermore, knocking out KAP1 remarkably increased the susceptibility of A549 cells to the anti-cancer drug 5-Fluorouracil, which correlated with increasing ERK phosphorylation. In vivo xenograft experiments suggested that KAP1 deficiency significantly decreases the tumorigenicity of A549 cells. Taken together, our findings indicate that KAP1 acts as a key module in the c-Raf-interactome complex and regulates lung cancer development through the Raf-MEK-ERK pathway. Therefore, KAP1 may represent a potential diagnosis biomarker and new treatment target for lung cancer.