Her4 promotes cancer metabolic reprogramming via the c-Myc-dependent signaling axis
Her4 promotes cancer metabolic reprogramming via the c-Myc-dependent signaling axis
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Her4 通过 c-Myc 依赖性信号轴促进癌症代谢重编程
DOI：
10.1016/j.canlet.2020.10.008
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发表时间：
2021-01-01
期刊：
影响因子：
9.7
通讯作者：
Cai, Zhengdong
中科院分区：
文献类型：
--
作者：
Han, Jing;Zhang, Yangfeng;Cai, Zhengdong
尽管在过去的几年中，代谢重编程作为癌症的一个重要标志越来越被认识到，但肿瘤发生过程中代谢改变的分子机制仍不清楚。在这项研究中，我们确定了Her 4在将癌症代谢重新连接到肿瘤促进代谢过程中的关键作用，包括增加糖酵解，氨解，线粒体生物合成和氧化磷酸化，这可能部分地合作促进肿瘤发生。我们发现Her 4的过表达通过CIP 2A介导的c-Myc（S62）磷酸化的增加和GSK 3 β介导的c-Myc（T58）磷酸化的减少促进c-Myc的稳定，这两者都减少了c-Myc的降解。此外，发现Her 4在骨肉瘤异种移植模型中增加葡萄糖摄取和肿瘤生长。总的来说，这些发现提供了对Her 4参与肿瘤发生的更好理解，并首次记录了其在代谢重编程中的潜在作用。我们相信，我们的研究可能会为癌症的靶向代谢治疗带来有希望的机会。
Despite the growing recognition of metabolic reprogramming as an important hallmark of cancer in the past few years, the molecular mechanisms underlying metabolic alterations during tumorigenesis remain unclear. In this study, we identified a critical role of Her4 in rewiring cancer metabolism toward tumor-promoting metabolic processes, including increased glycolysis, glutaminolysis, mitochondrial biogenesis, and oxidative phosphorylation, which may in part cooperate to promote tumorigenesis. We found that overexpression of Her4 promoted the stabilization of c-Myc through a CIP2A-mediated increase in c-Myc(S62) phosphorylation and GSK3 beta-mediated decrease in c-Myc(T58) phosphorylation, both of which decreased c-Myc degradation. Furthermore, Her4 was found to increase glucose uptake and tumor growth in an osteosarcoma xenograft model. Overall, these findings provide a better understanding of the involvement of Her4 in tumorigenesis and document its potential role in metabolic reprogramming for the first time. We believe that our study might lead to promising opportunities for targeted metabolic therapy for cancer.