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Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5687-5692. doi: 10.1073/pnas.1819869116. Epub 2019 Mar 6.

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

Author information

1
Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
2
Virginia Commonwealth University (VCU) Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
3
VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
4
Ludwig Institute for Cancer Research, University of California, San Diego, CA 92093 wcavenee@ucsd.edu paul.fisher@vcuhealth.org.
5
Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298; wcavenee@ucsd.edu paul.fisher@vcuhealth.org.

Abstract

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a multifunctional cytokine displaying broad-spectrum anticancer activity in vitro or in vivo in preclinical animal cancer models and in a phase 1/2 clinical trial in patients with advanced cancers. mda-7/IL-24 targets specific miRNAs, including miR-221 and miR-320, for down-regulation in a cancer-selective manner. We demonstrate that mda-7/IL-24, administered through a replication incompetent type 5 adenovirus (Ad.mda-7) or with His-MDA-7/IL-24 protein, down-regulates DICER, a critical regulator in miRNA processing. This effect is specific for mature miR-221, as it does not affect Pri-miR-221 expression, and the DICER protein, as no changes occur in other miRNA processing cofactors, including DROSHA, PASHA, or Argonaute. DICER is unchanged by Ad.mda-7/IL-24 in normal immortal prostate cells, whereas Ad.mda-7 down-regulates DICER in multiple cancer cells including glioblastoma multiforme and prostate, breast, lung, and liver carcinoma cells. MDA-7/IL-24 protein down-regulates DICER expression through canonical IL-20/IL-22 receptors. Gain- and loss-of-function studies confirm that overexpression of DICER rescues deregulation of miRNAs by mda-7/IL-24, partially rescuing cancer cells from mda-7/IL-24-mediated cell death. Stable overexpression of DICER in cancer cells impedes Ad.mda-7 or His-MDA-7/IL-24 inhibition of cell growth, colony formation, PARP cleavage, and apoptosis. In addition, stable overexpression of DICER renders cancer cells more resistant to Ad.mda-7 inhibition of primary and secondary tumor growth. MDA-7/IL-24-mediated regulation of DICER is reactive oxygen species-dependent and mediated by melanogenesis-associated transcription factor. Our research uncovers a distinct role of mda-7/IL-24 in the regulation of miRNA biogenesis through alteration of the MITF-DICER pathway.

KEYWORDS:

DICER; MITF; ROS; mda-7/IL-24; miRNA

PMID:
30842276
PMCID:
PMC6431152
[Available on 2019-09-19]
DOI:
10.1073/pnas.1819869116

Conflict of interest statement

Conflict of interest statement: W.K.C. and P.B.F. are cofounders of InterLeukin Combinatorial Therapies, Inc. (ILCT). W.K.C., P.B.F., and Virginia Commonwealth University own stock in ILCT. L.E. is the principal investigator of a sponsored research agreement provided by ILCT to Virginia Commonwealth University. The other authors declare no conflict of interest.

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