The miR-17∼92 microRNA Cluster Is a Global Regulator of Tumor Metabolism

Cell Rep. 2016 Aug 16;16(7):1915-28. doi: 10.1016/j.celrep.2016.07.036. Epub 2016 Aug 4.

Abstract

A central hallmark of cancer cells is the reprogramming of cellular metabolism to meet the bioenergetic and biosynthetic demands of malignant growth. Here, we report that the miR-17∼92 microRNA (miRNA) cluster is an oncogenic driver of tumor metabolic reprogramming. Loss of miR-17∼92 in Myc(+) tumor cells leads to a global decrease in tumor cell metabolism, affecting both glycolytic and mitochondrial metabolism, whereas increased miR-17∼92 expression is sufficient to drive increased nutrient usage by tumor cells. We mapped the metabolic control element of miR-17∼92 to the miR-17 seed family, which influences cellular metabolism and mammalian target of rapamycin complex 1 (mTORC1) signaling through negative regulation of the LKB1 tumor suppressor. miR-17-dependent tuning of LKB1 levels regulates both the metabolic potential of Myc(+) lymphomas and tumor growth in vivo. Our results establish metabolic reprogramming as a central function of the oncogenic miR-17∼92 miRNA cluster that drives the progression of MYC-dependent tumors.

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Gene Expression Regulation, Neoplastic*
  • Glycolysis / genetics
  • Heterografts
  • Humans
  • Lymphocyte Transfusion
  • Lymphocytes / metabolism*
  • Lymphocytes / pathology
  • Lymphoma / genetics
  • Lymphoma / metabolism*
  • Lymphoma / pathology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Oxidative Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Long Noncoding
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • MIR17HG, human
  • MYC protein, human
  • MicroRNAs
  • Multiprotein Complexes
  • Proto-Oncogene Proteins c-myc
  • RNA, Long Noncoding
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinase Kinases