Oncogenic MYC Activates a Feedforward Regulatory Loop Promoting Essential Amino Acid Metabolism and Tumorigenesis

• DOI: 10.1016/j.celrep.2017.12.002
• Publication Date: 2017-12-26T16:43:34Z
• Authors: Ming Yue; Jue Jiang; Peng Gao; Hudan Liu; Guoliang Qing
• Keywords: Reprogramming; Proto-Oncogene Proteins c-myc

Most tumor cells exhibit obligatory demands for essential amino acids (EAAs), but the regulatory mechanisms whereby take up EAAs and promote malignant transformation remain to be determined. Here, we show that oncogenic MYC, solute carrier family (SLC) 7 member 5 (SLC7A5), SLC43A1 constitute a feedforward activation loop EAA transport tumorigenesis. MYC selectively activates Slc7a5 Slc43a1 transcription through direct binding specific E box elements within both genes, enabling effective import. Elevated EAAs, in turn, stimulate Myc mRNA translation, part attenuation of GCN2-eIF2α-ATF4 acid stress response pathway, leading MYC-dependent transcriptional amplification. SLC7A5/SLC43A1 depletion inhibits expression, metabolic reprogramming, cell growth vitro vivo. These findings thus reveal MYC-SLC7A5/SLC43A1 signaling circuit underlies metabolism, deregulation,