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MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF

Anjan K Pradhan1, Praveen Bhoopathi1, Sarmistha Talukdar1

  • 1Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.

Proceedings of the National Academy of Sciences of the United States of America
|March 8, 2019
PubMed

Insights

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) targets DICER, a key miRNA processing enzyme, in cancer cells. This regulation, dependent on reactive oxygen species and MITF, impacts cancer cell death and tumor growth.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Gene Therapy

Background:

  • Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) exhibits broad-spectrum anticancer activity.
  • mda-7/IL-24 selectively targets specific microRNAs (miRNAs) for downregulation in cancer cells.
  • The precise mechanisms underlying mda-7/IL-24's anticancer effects, particularly its impact on miRNA biogenesis, require further elucidation.

Purpose of the Study:

  • To investigate the role of mda-7/IL-24 in regulating miRNA processing, focusing on DICER.
  • To determine the cancer-selective nature of mda-7/IL-24-mediated DICER downregulation.
  • To explore the downstream consequences of DICER modulation by mda-7/IL-24 on cancer cell behavior and tumor growth.

Main Methods:

  • Administration of mda-7/IL-24 via adenovirus (Ad.mda-7) or protein to cancer and normal cells.
  • Analysis of DICER, DROSHA, PASHA, and Argonaute expression levels.
  • Gain- and loss-of-function studies involving DICER overexpression.
  • Assessment of cell viability, apoptosis, colony formation, and tumor growth inhibition.
  • Investigation of reactive oxygen species (ROS) dependence and the role of melanogenesis-associated transcription factor (MITF).

Main Results:

  • mda-7/IL-24, delivered by Ad.mda-7 or protein, specifically downregulates DICER in various cancer cells but not normal prostate cells.
  • This downregulation affects mature miR-221 but not Pri-miR-221, and is mediated through IL-20/IL-22 receptors.
  • Overexpression of DICER rescues miRNA deregulation, partially protects cancer cells from mda-7/IL-24-induced cell death, and confers resistance to growth inhibition and tumor growth suppression.
  • mda-7/IL-24's regulation of DICER is ROS-dependent and involves the MITF pathway.

Conclusions:

  • mda-7/IL-24 regulates miRNA biogenesis by downregulating DICER in a cancer-selective manner.
  • The MITF-DICER pathway is a novel target for mda-7/IL-24's anticancer activity.
  • Modulating DICER levels influences cancer cell sensitivity to mda-7/IL-24 therapy, suggesting potential therapeutic strategies.
Keywords:
DICERMITFROSmda-7/IL-24miRNA

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