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The mechanisms that underpin physiological adaptation of pancreatic ductal adenocarcinoma cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. We find transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins, based on transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor trametinib. c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression under baseline conditions. MiT/TFE-dependent lysosome biogenesis is a process that contributes to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and improved mitochondrial respiration. During adaptation to KRAS-MAPK inhibition, according to Shunning iron utilization, lowering iron use sensitizes PDA cells to MEKi, undermining a critical and targetable reliance on lysosome-dependent iron supply. Significance Lower c-MYC levels following MAPK pathway suppression may have aided in the upregulation of autophagy and lysosome biogenesis.
Source link: https://europepmc.org/article/MED/35771494
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