Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA

Oncotarget. 2015 Feb 10;6(4):2451-65. doi: 10.18632/oncotarget.3235.


Let-7 microRNAs (miRNAs) are highly conserved well-established promoters of terminal differentiation that are expressed in healthy adult tissues and frequently repressed in cancer cells. The tumor suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. In this study we described a new role of let-7a in reprogramming cancer metabolism, recently identified as a new hallmark of cancer. We show that let-7a down-regulates key anabolic enzymes and increases both oxidative phosphorylation and glycolysis in triple-negative breast cancer and metastatic melanoma cell lines. Strikingly, the accelerated glycolysis coexists with drastically reduced cancer features. Moreover, let-7a causes mitochondrial ROS production concomitant with the up-regulation of oxidative stress responsive genes. To exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the chemotherapeutic drug doxorubicin. In both cancer types let-7a increased cell sensitivity to doxorubicin. Pre-treatment with N-acetyl cysteine (NAC) totally abolished this effect, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We thus have demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells, further expanding its therapeutic potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cellular Reprogramming / genetics*
  • Doxorubicin / pharmacology
  • Energy Metabolism / genetics*
  • Enzymes / genetics
  • Enzymes / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Glycolysis / genetics
  • Humans
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Neoplasm Metastasis
  • Oxidative Phosphorylation
  • Oxidative Stress / genetics
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction


  • Enzymes
  • MicroRNAs
  • Reactive Oxygen Species
  • mirnlet7 microRNA, human
  • Doxorubicin