EGR1 interacts with TBX2 and functions as a tumor suppressor in rhabdomyosarcoma.
EGR1 interacts with TBX2 and functions as a tumor suppressor in rhabdomyosarcoma.
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DOI：
10.18632/oncotarget.24726
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发表时间：
2018-04-06
期刊：
影响因子：
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通讯作者：
Davie JK
中科院分区：
文献类型：
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作者：
Mohamad T;Kazim N;Adhikari A;Davie JK
EGR1是一种即时早期反应基因，在癌症中可以作为肿瘤抑制基因或致癌基因发挥作用。EGR1在横纹肌肉瘤（rhabdomyosarcoma， RMS）（一种源自肌肉系的儿童癌症）中的功能尚未完全确定。我们发现EGR1在肺泡RMS （ARMS）亚型中下调，但在胚胎RMS （ERMS）中表达水平与正常骨骼肌相当。我们发现，在ARMS中过表达EGR1可显著降低细胞增殖、移动性和非锚定生长，同时促进分化。我们发现EGR1与TBX2相互作用，我们已经证明TBX2在RMS中具有致癌基因的功能。这种相互作用抑制EGR1依赖基因的表达，包括细胞周期调节因子p21和PTEN以及其他重要的细胞生长驱动因子，如NDRG1和CST6。我们还发现EGR1通过触发内在凋亡通路诱导细胞凋亡。EGR1还激活了两种促凋亡因子，BAX和去磷酸化的BAD，它们都位于内在途径中caspase级联的上游。EGR1还使RMS细胞对化疗药物敏感，这表明激活EGR1可能通过诱导细胞凋亡来提高治疗靶向性。我们的研究结果确立了EGR1在理解RMS病理中的重要作用。
EGR1, one of the immediate-early response genes, can function as a tumor suppressor gene or as an oncogene in cancer. The function of EGR1 has not been fully characterized in rhabdomyosarcoma (RMS), a pediatric cancer derived from the muscle linage. We found that EGR1 is downregulated in the alveolar RMS (ARMS) subtype but expressed at levels comparable to normal skeletal muscle in embryonal RMS (ERMS). We found that overexpression of EGR1 in ARMS significantly decreased cell proliferation, mobility, and anchorage-independent growth while also promoting differentiation. We found that EGR1 interacts with TBX2, which we have shown functions as an oncogene in RMS. The interaction inhibits EGR1 dependent gene expression, which includes the cell cycle regulators p21 and PTEN as well as other important cell growth drivers such as NDRG1 and CST6. We also found that EGR1 induced apoptosis by triggering the intrinsic apoptosis pathway. EGR1 also activated two pro-apoptotic factors, BAX and dephosphorylated BAD, which are both located upstream of the caspase cascades in the intrinsic pathway. EGR1 also sensitized RMS cells to chemotherapeutic agents, suggesting that activating EGR1 may improve therapeutic targeting by inducing apoptosis. Our results establish the important role of EGR1 in understanding RMS pathology.