MicroRNA-26a Is Strongly Downregulated in Melanoma and Induces Cell Death through Repression of Silencer of Death Domains (SODD)

Abstract

Melanoma is an aggressive cancer that metastasizes rapidly, and is refractory to conventional chemotherapies. Identifying miRNAs that are responsible for this pathogenesis is therefore a promising means of developing new therapies. We identified miR-26a through microarray and qRT-PCR experiments as an miRNA that is strongly down-regulated in melanoma cell lines as compared to primary melanocytes. Treatment of cell lines with miR-26a mimic caused significant and rapid cell death compared to a negative control in most melanoma cell lines tested. In surveying targets of miR-26a, we found that protein levels of SMAD1 and BAG-4/SODD were strongly decreased in sensitive cells treated with miR-26a mimic compared to the control. The luciferase reporter assays further demonstrated that miR-26a can repress gene expression through the binding site in the 3′UTR of SODD. Knockdown of these proteins with siRNA showed that SODD plays an important role in protecting melanoma cells from apoptosis in most cell lines sensitive to miR-26a, while SMAD1 may play 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.

MicroRNAs as an Emerging Target for Melanoma Therapy

“…In the current manuscript from Reuland et al (2013), transfection of miR-26a mimics in multiple melanoma cell lines resulted in increased cell death, which did not occur in primary melanocytes. Among the known targets of miR-26a, only SMAD1 exhibited a consistent repression at the translational level during miR-26a mimic treatment of melanoma cell lines.…”

“…Despite the growing focus on microRNAs (miRNAs) as novel diagnostic tools and therapeutic targets in cancer, global characterization of miRNA expression patterns and their specific targets in melanoma has lagged. In this issue, Reuland et al (2013) identify miR-26a as being specifically downregulated in human melanoma cells. They further establish Silencer of Death Domains as a novel target for miR-26a, which functionally mediates melanoma cell death.…”

“…Despite mounting data linking miRNAs to melanomagenesis, few melanoma-associated miRNAs have as yet been characterized in depth. In this issue of the Journal of Investigative Dermatology, Reuland et al (2013) provide important new insights into miRNAs involved in melanoma progression and their potential therapeutic utility. Through a microarray screen of miRNAs associated with melanoma cell lines versus primary melanocytes, the authors identify miR26a as being significantly downregulated during melanoma development.…”

Long non-coding RNA MINCR promotes gallbladder cancer progression through stimulating EZH2 expression

“…The mechanism of suppression included inhibiting cells from G1/S transition [40], inducing cell-cycle arrest associated with direct targeting of cyclins D2 and E2 [41], and targeting gene HMGA1, estrogen receptor-α, or EZH2 [35,42,43]. EZH2 targeting by miR-26a has been widely reported to be involved in nasopharyngeal carcinoma [28], rhabdomyosarcoma [44], breast cancer [45], prostate cancer [46], melanoma [47], myeloid leukemia [48], hepatocellular carcinoma [49], and human lung carcinoma cells [50]. We found that miR-26a-5p could repress the expression of EZH2 in GBC cells, which is consistent with above reports.…”

MiR-26a modulates extracellular matrix homeostasis in cartilage

“…MiRNA-26a can regulate cell proliferation [11] and survival of various cells [12] by targeting the expression of cell cycle and cell survival genes, but we observed only a minor effect of mimic or inhibitor transfection on PEC proliferation and survival. This indicates that both processes may not be main targets of miR-26a action in chondrocytes.…”