MicroRNA-26a is strongly downregulated in melanoma and induces cell death through repression of silencer of death domains (SODD)

Steven N. Reuland, Shilo M. Smith, Lynne T. Bemis, Nathaniel B. Goldstein, Adam R. Almeida, Katie A. Partyka, Victor E. Marquez, Qinghong Zhang, David A. Norris, Yiqun G. Shellman

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Melanoma is an aggressive cancer that metastasizes rapidly and is refractory to conventional chemotherapies. Identifying microRNAs (miRNAs) that are responsible for this pathogenesis is therefore a promising means of developing new therapies. We identified miR-26a through microarray and quantitative reverse-transcription-PCR (qRT-PCR) experiments as an miRNA that is strongly downregulated in melanoma cell lines as compared with primary melanocytes. Treatment of cell lines with miR-26a mimic caused significant and rapid cell death compared with a negative control in most melanoma cell lines tested. In surveying targets of miR-26a, we found that protein levels of SMAD1 (mothers against decapentaplegic homolog 1) and BAG-4/SODD were strongly decreased in sensitive cells treated with miR-26a mimic as compared with the control. The luciferase reporter assays further demonstrated that miR-26a can repress gene expression through the binding site in the 3′ untranslated region (3′UTR) of SODD (silencer of death domains). Knockdown of these proteins with small interfering RNA (siRNA) showed that SODD has an important role in protecting melanoma cells from apoptosis in most cell lines sensitive to miR-26a, whereas SMAD1 may have a minor role. Furthermore, transfecting cells with a miR-26a inhibitor increased SODD expression. Our findings indicate that miR-26a replacement is a potential therapeutic strategy for metastatic melanoma, and that SODD, in particular, is a potentially useful therapeutic target.

Original languageEnglish (US)
Pages (from-to)1286-1293
Number of pages8
JournalJournal of Investigative Dermatology
Volume133
Issue number5
DOIs
StatePublished - May 2013

Bibliographical note

Funding Information:
This work was supported in part by NIAMS grant R01AR26427-18 to DAN; by a Veterans Administration merit grant from the Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development) to DAN; by NIH training grant 5T32AR007411-29 to SNR (PI: DAN); by a Southwestern Skin Cancer SPORE Pilot project to YGS; and by the Intramural Research Program of the NIH, National Cancer Institute for Cancer Research, to VEM. We thank Karen Helm, Christine Childs, and Alistaire S Acosta at the University of Colorado Cancer Center Flo w Cytometry Core (supported by NIH grant P30 CA 046934) and Bifeng Gao at the University of Colorado Microarray Core for their expert technical assistance.

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