PTEN ceRNAs in melanoma

Pier Paolo Pandolfi and colleagues recently hypothesized that protein-coding RNA transcripts can compete for and sequester microRNAs (miRNAs), and they call these RNA transcripts competing endogenous RNAs (ceRNAs). In two recent studies, Pandolfi and colleagues identify ceRNAs that regulate the tumor suppressor PTEN and can promote melanoma in a mouse model (Cell 147, 344–357, 2011, and Cell 147, 382–395, 2011). The authors performed a Sleeping Beauty transposon screen to search for genes that promote melanoma in a B-RAF^V619E mouse. They identified 320 common insertion sites and searched for genes enriched for miRNA recognition elements (MREs) shared with PTEN. They identified 33 putative ceRNAs affecting PTEN and depleted them using RNA interference in human melanoma cells; the decreased levels of six of the putative ceRNAs reduced PTEN mRNA levels. None of the putative PTEN ceRNAs encode known tumor suppressors, but one gene identified, ZEB2, encodes an activator of the epithelial-to-mesenchymal transition (EMT). To test whether the regulation of PTEN by ZEB2 depends on miRNA, the authors depleted ZEB2 in a Dicer-null cell line. They found that ZEB2 knockdown did not affect PTEN mRNA levels, indicating that ZEB2 regulation of PTEN does depend on miRNA. Using bioinformatic analysis and RNA immunoprecipitations, the authors show that the ZEB2 transcript binds at least four miRNAs in the regulation of PTEN expression.