Transcriptional control of the autophagy-lysosome system in pancreatic cancer
Perera, Rushika M.
Nicolay, Brandon N.
Selig, Martin K.
Bardeesy, NabeelNote: Order does not necessarily reflect citation order of authors.
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CitationPerera, R. M., S. Stoykova, B. N. Nicolay, K. N. Ross, J. Fitamant, M. Boukhali, J. Lengrand, et al. 2016. “Transcriptional control of the autophagy-lysosome system in pancreatic cancer.” Nature 524 (7565): 361-365. doi:10.1038/nature14587. http://dx.doi.org/10.1038/nature14587.
AbstractActivation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers1. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy2–4, a conserved self-degradative process5. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. We now 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 transcription factors. In PDA cells, the MiT/TFE proteins6 – 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-lysosomal activation is specifically required to maintain intracellular amino acid (AA) pools. These results identify the MiT/TFE transcription factors as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate activation of clearance pathways converging on the lysosome as a novel hallmark of aggressive malignancy.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:29408275
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