Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism

Article

关键词: NUCLEAR IMPORT;    GENOMIC ANALYSES;    TUMOR-GROWTH;    PROTEIN;    BIOGENESIS;    CELLS;    MTOR;    TFEB;    P53;    CLEARANCE;   

DOI  :  10.1038/nature14587

来源: SCIE

【 摘 要 】

Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers(1). The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy(2-4), a conserved self-degradative process(5). However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins(6)-MITF, TFE3 and TFEB-are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.

【 授权许可】

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