MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor-1.
MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor-1.
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DOI：
10.7554/elife.60191
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发表时间：
2021-01-08
期刊：
影响因子：
7.7
通讯作者：
Tansey WP
中科院分区：
文献类型：
--
作者：
Popay TM;Wang J;Adams CM;Howard GC;Codreanu SG;Sherrod SD;McLean JA;Thomas LR;Lorey SL;Machida YJ;Weissmiller AM;Eischen CM;Liu Q;Tansey WP
癌蛋白转录因子MYC是恶性肿瘤的主要驱动因素，也是开发抗癌疗法的高度有效但具有挑战性的靶点。抑制MYC的新策略可能来自于了解它用于驱动促肿瘤基因表达程序的辅助因子，前提是了解它们在MYC活性中的作用。在这里，我们询问如何一个MYC辅因子，宿主细胞因子（HCF）-1，有助于MYC活性在人类伯基特淋巴瘤设置。我们确定了与线粒体功能和核糖体生物发生相关的基因作为直接MYC/HCF-1靶点，并证明了MYC-HCF-1相互作用的调节如何影响细胞生长，代谢产物谱，全球基因表达模式和体内肿瘤生长。这项工作将HCF-1定义为一种关键的MYC辅因子，将MYC-HCF-1相互作用置于生物学背景下，并强调HCF-1是开发新型抗MYC疗法的焦点。当细胞失去对其生长的控制时，肿瘤就形成了。通常，细胞会产生信号来控制它们分裂的数量和频率。但是如果这些信号出现故障，细胞可能会生长得太快或繁殖得太频繁。例如，一组被称为MYC蛋白的蛋白质激活细胞中的生长基因，但过多的这些蛋白质会导致细胞不受控制地生长。由于三分之一的癌症死亡与过量的MYC蛋白有关，这些分子可能是抗癌药物的关键靶点。然而，目前的治疗未能靶向这些蛋白质。治疗与MYC蛋白相关的癌症的一种选择可能是靶向与MYC蛋白一起工作的蛋白质，例如可以附着于MYC蛋白的蛋白质HCF-1。为了测试HCF-1是否可能成为潜在的药物靶点，Popay等人首先使用实验室中生长的特定癌细胞研究了HCF-1和MYC蛋白如何相互作用。这表明，当两种蛋白质连接时，它们激活了触发细胞快速生长的基因。当这些癌细胞被注射到小鼠体内时，肿瘤迅速生长。然而，当癌细胞中的MYC和HCF-1附着被破坏时，肿瘤就会缩小。这表明，如果抗癌药物能够靶向HCF-1蛋白，它们可能会减少甚至逆转肿瘤的生长。虽然还需要进一步的研究来确定候选药物，但这些发现揭示了一个有希望的靶点，用于治疗由过度丰富的MYC蛋白引起的肿瘤。
The oncoprotein transcription factor MYC is a major driver of malignancy and a highly validated but challenging target for the development of anticancer therapies. Novel strategies to inhibit MYC may come from understanding the co-factors it uses to drive pro-tumorigenic gene expression programs, providing their role in MYC activity is understood. Here we interrogate how one MYC co-factor, host cell factor (HCF)–1, contributes to MYC activity in a human Burkitt lymphoma setting. We identify genes connected to mitochondrial function and ribosome biogenesis as direct MYC/HCF-1 targets and demonstrate how modulation of the MYC–HCF-1 interaction influences cell growth, metabolite profiles, global gene expression patterns, and tumor growth in vivo. This work defines HCF-1 as a critical MYC co-factor, places the MYC–HCF-1 interaction in biological context, and highlights HCF-1 as a focal point for development of novel anti-MYC therapies. Tumours form when cells lose control of their growth. Usually, cells produce signals that control how much and how often they divide. But if these signals become faulty, cells may grow too quickly or multiply too often. For example, a group of proteins known as MYC proteins activate growth genes in a cell, but too much of these proteins causes cells to grow uncontrollably. With one third of all cancer deaths linked to excess MYC proteins, these molecules could be key targets for anti-cancer drugs. However, current treatments fail to target these proteins. One option for treating cancers linked to MYC proteins could be to target proteins that work alongside MYC proteins, such as the protein HCF-1, which can attach to MYC proteins. To test if HCF-1 could be a potential drug target, Popay et al. first studied how HCF-1 and MYC proteins interacted using specific cancer cells grown in the laboratory. This revealed that when the two proteins connected, they activated genes that trigger rapid cell growth. When these cancer cells were then injected into mice, tumours quickly grew. However, when the MYC and HCF-1 attachments in the cancer cells were disrupted, the tumours shrunk. This suggests that if anti-cancer drugs were able to target HCF-1 proteins, they could potentially reduce or even reverse the growth of tumours. While further research is needed to identify drug candidates, these findings reveal a promising target for treating tumours that stem from over-abundant MYC proteins.