Myc 的失调需要 MondoA/Mlx 进行代谢重编程和肿瘤发生。
Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis.
机构信息
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, MS A2-025, P.O. Box 19024, Seattle, WA 98109-1024, USA.
Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Room S148, P.O. Box 358057, Seattle, WA 98109-8057, USA.
出版信息
Cancer Cell. 2015 Feb 9;27(2):271-85. doi: 10.1016/j.ccell.2014.11.024. Epub 2015 Jan 29.
Abstract
Deregulated Myc transcriptionally reprograms cell metabolism to promote neoplasia. Here we show that oncogenic Myc requires the Myc superfamily member MondoA, a nutrient-sensing transcription factor, for tumorigenesis. Knockdown of MondoA, or its dimerization partner Mlx, blocks Myc-induced reprogramming of multiple metabolic pathways, resulting in apoptosis. Identification and knockdown of genes coregulated by Myc and MondoA have allowed us to define metabolic functions required by deregulated Myc and demonstrate a critical role for lipid biosynthesis in survival of Myc-driven cancer. Furthermore, overexpression of a subset of Myc and MondoA coregulated genes correlates with poor outcome of patients with diverse cancers. Coregulation of cancer metabolism by Myc and MondoA provides the potential for therapeutics aimed at inhibiting MondoA and its target genes.
摘要
失调的 Myc 通过重编程细胞代谢来促进肿瘤发生。在这里，我们表明致癌 Myc 需要 Myc 超家族成员 MondoA（一种营养感应转录因子）才能发生肿瘤。MondoA 或其二聚化伙伴 Mlx 的敲低会阻断 Myc 诱导的多种代谢途径的重编程，导致细胞凋亡。鉴定和敲低 Myc 和 MondoA 共同调控的基因，使我们能够确定失调 Myc 所需的代谢功能，并证明脂质生物合成在 Myc 驱动的癌症存活中起关键作用。此外，一组 Myc 和 MondoA 共同调控基因的过表达与多种癌症患者的不良预后相关。Myc 和 MondoA 对癌症代谢的共同调控为靶向抑制 MondoA 及其靶基因的治疗提供了可能。
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