Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma
Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma
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DOI：
10.1182/blood-2014-06-584524
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发表时间：
2014-09-25
期刊：
影响因子：
20.3
通讯作者：
Keller, Ulrich
中科院分区：
文献类型：
--
作者：
Hoellein, Alexander;Fallahi, Mohammad;Keller, Ulrich
Myc致癌转录因子（c-Myc、N-Myc和L-Myc）协调控制细胞生长、分裂和代谢。在癌症中，Myc过表达通常与侵袭性疾病相关，部分原因是泛素-蛋白酶体系统破坏了选择的靶标（例如，SCFSkp2定向破坏Cdk抑制剂p27(Kip1)）。我们推断Myc也会调节SUMOylation，这是一种相关的蛋白质翻译后修饰手段，并且该回路将在Myc依赖性肿瘤发生中发挥重要作用。在这里，我们报道了在小鼠和人类myc驱动的淋巴瘤中，编码SUMOylation机制的调节因子和成分的基因的表达显著增加，导致这些肿瘤中的超SUMOylation。此外，通过遗传手段抑制SUMOylation会使myc诱导的增殖失效，引发G2/M细胞周期阻滞、多倍体和凋亡。使用基因定义细胞模型和条件表达系统，这种反应被证明是Myc特异性的。最后，体内功能丧失和药理学研究表明，抑制SUMOylation可促进myc驱动淋巴瘤的快速消退。因此，靶向SUMOylation对于MYC累及的淋巴瘤是一种有吸引力的治疗选择。
Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCFSkp2 -directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement.