The VIMM, established in 2008 by Paul B. Fisher, M.Ph., Ph.D., the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by the VIMM members.     

MDA-7/IL-24 suppresses DICER

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

 

MicroRNAs (miRNAs) are small 19-22 nt noncoding RNAs that are essential controllers of normal development and regulators of diverse diseases, including cancer, cardiovascular and neurodegenerative diseases. Melanoma differentiation associated gene-7/Interleukin-24 ( mda-7/IL-24 ), a cancer-selective apoptosis-inducing cytokine has established anti-cancer activity in vitro and in vivo in preclinical animal models. Intratumoral injection of an adenovirus expressing mda-7/IL-24 (Ad. mda-7 ; INGN 241), in a phase I/II clinical trial of advanced cancers, demonstrated its therapeutic efficacy. Previous work by the Fisher laboratory discovered a novel and unique role of mda-7/ IL-24 in regulating expression of several miRNAs, including miR-221, a key microRNA in many cancers. The current study further extends this observation and provides important molecular insights through detailed in vitro and in vivo experiments on how mda-7/IL-24 regulates the miRNA biogenesis process. This study demonstrates that mda-7/IL-24 effectively downregulates a key miRNA processing enzyme, DICER in a cancer selective manner, thereby deregulating miRNA expression. Gain- and loss-of-function studies confirm that overexpression of DICER rescues deregulation of miRNAs by mda-7/IL-24 , reducing mda-7/IL-24- mediated cell death of cancer cells. MDA-7/IL-24-mediated DICER deregulation occurs in a reactive oxygen species (ROS)-dependent manner through regulation of melanogenesis-associated transcription factor (MITF). A link between mda-7/IL-24 , DICER, and reactive oxygen species in cancer cells is described that might be exploited to produce enhanced and effective therapies for cancer.

Anjan K Pradhan, a postdoctoral research scientist in Dr. Paul Fisher’s laboratory at VCU, is the lead author of this paper, and performed much of the biological and animal work. The study was published in the Proceedings of the National Academy of Sciences of the United States of America on March 19, 2019*. The present study was supported in part by the National Cancer Institute Cancer Center Support Grant to the VCU Massey Cancer Center P30 CA016059 (to P.B. Fisher and D. Sarkar), the National Foundation for Cancer Research (to P.B. Fisher and W.K. Cavenee), the VCU Institute of Molecular Medicine (to P.B. Fisher) and the VCU Genetics Enhancement Fund (to P.B. Fisher, S.K. Das, and L. Emdad). Support was also provided by a Sponsored Research Agreement from InterLeukin Combinatorial Therapies ( ILCT ) (to L. Emdad).

Figure legend: Schematic representation of regulation of the miRNA processing enzyme DICER by mda-7/IL-24. MDA-7/IL-24 down regulates the transcription factor MITF in a ROS-dependent manner which in turn downregulates DICER.

Publications:

Pradhan AK, Talukdar S, Bhoopathi P, Shen XN, Emdad L, Das SK, Sarkar D, Fisher PB (2017) mda-7/IL-24 Mediates Cancer Cell-Specific Death via Regulation of miR-221 and the Beclin-1 Axis. Cancer Res. 2017 Feb 15;77(4):949-959. PMCID: PMC5313338



*Pradhan AK, Bhoopathi P, Talukdar S, Scheunemann D, Sarkar D, Cavenee WK, Das SK, Emdad L, Fisher PB. MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF. Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5687-5692. DOI: 10.1073/pnas.1819869116

 

About the Investigators: Paul B. Fisher, MPh, PhD, FNAI, is Professor and Chair of the VCU Department of Human and Molecular Genetics (HMG), Director of the VCU Institute of Molecular Medicine (VIMM) and Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Webster K. Cavenee, PhD is Director of Strategic Alliances in Central Nervous System (CNS) Cancers, Distinguished Professor UCSD and Member of the Ludwig Institute of Cancer Research, UCSD. Anjan Pradhan, PhD, is the lead author of this research study, and along with Sarmistha Talukdar, PhD are postdoctoral research scientists in HMG. Praveen Bhoopathi, PhD is an Instructor in HMG. Swadesh K. Das, PhD, and Luni Emdad, MBBS, PhD are Assistant Professors in HMG and Members of the VIMM. Devanand Sarkar is a Professor in HMG, Associate Scientific Director of Therapeutics in the VIMM, and a Harrison Foundation Distinguished Professor in Cancer Research in the VCU MCC. Danielle Scheunemann is a Master’s student in HMG.