MicroRNA 211 Functions as a Metabolic Switch in Human Melanoma Cells

Abstract

bMicroRNA 211 (miR-211) negatively regulates genes that drive invasion of metastatic melanoma. Compared to normal human melanocytes, miR-211 expression is significantly reduced or absent in nonpigmented melanoma cells and lost during human melanoma progression. To investigate the molecular mechanism of its tumor suppressor function, miR-211 was ectopically expressed in nonpigmented melanoma cells. Ectopic expression of miR-211 reduced hypoxia-inducible factor 1␣ (HIF-1␣) protein levels and decreased cell growth during hypoxia. HIF-1␣ protein loss was correlated with the downregulation of a miR-211 target gene, pyruvate dehydrogenase kinase 4 (PDK4). We present evidence that resumption of miR-211-mediated downregulation of PDK4 in melanoma cells causes inhibition of invasion by nonpigmented melanomas via HIF-1␣ protein destabilization. Thus, the tumor suppressor miR-211 acts as a metabolic switch, and its loss is expected to promote cancer hallmarks in human melanomas. Melanoma, one of the deadliest forms of skin cancer, kills nearly 10,000 people in the United States per year. We had previously shown that a small noncoding RNA, termed miR-211, suppresses invasion and the growth of aggressive melanoma cells. The results presented here support the hypothesis that miR-211 loss in melanoma cells causes abnormal regulation of energy metabolism, which in turn allows cancer cells to survive under low oxygen concentrations-a condition that generally kills normal cells. These findings highlight a novel mechanism of melanoma formation: miR-211 is a molecular switch that is turned off in melanoma cells, raising the hope that in the future we might be able to turn the switch back on, thus providing a better treatment option for melanoma.

BRAFV600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

“…It was further suggested that miR-211 acts as a molecular switch that is usually turned off in many melanomas, and figuring out how and when to turn this switch on might provide insights into better treatment for melanomas (29,30). Our finding that miR-211-5p is increased in cells upon vemurafenib treatment could support the development of more targeted therapies against melanoma cells in which miR-211 is up-regulated.…”

“…Additionally, miR-211 has been shown to function as a metabolic switch in melanoma cells by targeting the hypoxia inducible factor 1α (HIF-1α), and loss of miR-211-5p is expected to promote cancer hallmarks in human melanomas (29). It was further suggested that miR-211 acts as a molecular switch that is usually turned off in many melanomas, and figuring out how and when to turn this switch on might provide insights into better treatment for melanomas (29,30).…”

NF-κB-Induced MicroRNA-211 Inhibits Interleukin-10 in Macrophages of Rats with Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

“…For example, Mazar et al demonstrated that miR-211 functioned as a metabolic switch in human melanoma cells [24]. In a case-control study, Sumbul et al reported that miR-211 was up-regulated and associated with the poor prognosis in colorectal cancers [25].…”

Identification of microRNAs associated with invasive and aggressive phenotype in cutaneous melanoma by next-generation sequencing

“…18 Among them was miR-211 whose expression was significantly decreased in melanomas compared with common nevi in an independent, validation cohort. 18 miR-211 functions as a metabolic switch 19 and as a potent tumor suppressor in vitro influencing gene pathways involved in cell invasion. [20][21][22] It is located within the noncoding sequence (intron 6) of Melastatin-1 (MLSN-1) gene, 20 which is expressed at high levels in melanocytic nevi but significantly reduced in metastatic melanomas with variable expression in primary lesions.…”