Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Shanghai Medical College; Key Laboratory of Breast Cancer in Shanghai; Innovation Center for Cell Signaling Network; Cancer Institutes, Fudan University, 200032, Shanghai, China.
School of Life Science, The CAS Key Laboratory of Innate Immunity and Chronic Disease, University of Science and Technology of China, 230027, Hefei, Anhui, China.
Cell Death Dis. 2018 Nov 16;9(12):1143. doi: 10.1038/s41419-018-1201-x.
Myristoylation is one of key post-translational modifications that involved in signal transduction, cellular transformation and tumorigenesis. Increasing evidence demonstrates that targeting myristoylation might provide a new strategy for eliminating cancers. However, the underlying mechanisms are still yielded unclear. In this study, we demonstrated that genetic inhibition of N-myristoyltransferase NMT1 suppressed initiation, proliferation and invasion of breast cancer cells either in vitro or in vivo. We identified ROS could negatively regulate NMT1 expression and NMT1 knockdown conversely promoted oxidative stress, which formed a feedback loop. Furthermore, inhibition of NMT1 caused degraded proteins increase and ER stress, which cross-talked with mitochondria to produce more ROS. And both of oxidative stress and ER stress could activate JNK pathway, leading to autophagy which abrogated breast cancer progression especially triple-negative breast cancer (TNBC). These studies provide a preclinical proof of concept for targeting NMT1 as a strategy to treat breast cancer.
豆蔻酰化是一种关键的翻译后修饰，涉及信号转导、细胞转化和肿瘤发生。越来越多的证据表明，靶向豆蔻酰化可能为消除癌症提供一种新策略。然而，其潜在机制尚不清楚。在这项研究中，我们证明了遗传抑制 N-豆蔻酰转移酶 NMT1 无论是在体外还是体内都能抑制乳腺癌细胞的起始、增殖和侵袭。我们发现 ROS 可以负向调节 NMT1 的表达，而 NMT1 的敲低则促进了氧化应激，形成了一个反馈环。此外，抑制 NMT1 导致降解蛋白增加和内质网应激，这与线粒体相互作用产生更多的 ROS。氧化应激和内质网应激都可以激活 JNK 通路，导致自噬，从而阻止乳腺癌的进展，尤其是三阴性乳腺癌（TNBC）。这些研究为靶向 NMT1 作为治疗乳腺癌的策略提供了临床前概念验证。
