Another myc in the wall: MicroRNA‐101 controls important functions in liver cancer formation

T he hepatocellular carcinoma (HCC) field has witnessed major progress in recent years. However, since the introduction of sorafenib into the treatment of advanced disease, no additional compound has been approved for firstor second-line treatment. These failed trials make it increasingly clear that we need to understand the pathophysiology of HCC in the utmost detail to further the development of new drugs and to, perhaps more significant, assign the right patients to the right trials. In this issue of HEPATOLOGY, Wang et al. give us insight into how complex the mechanisms that control liver cancer formation really are. In their work, they construct a model in which the dysregulation of a microRNA (miRNA; mir-101) changes the expression of a set of important genes that all influence the malignant potential of HCC cells. Moreover, the expression of this miRNA is under the control of several proteins that regulate each other in feedback loops, thus giving small changes in expression levels enormous leverage. Analysis of dys-regulated miRNA expression in cancer cells is increasingly used for classification of tumors and might also have prognostic value in certain dieseases. In HCC, the expression patterns of miRNAs have been used to differentiate tumor tissue from normal liver, subclassify different types of HCC, and make predictions on recurrence after surgery. Functionally, miRNAs can have tumor-suppressive or oncogenic functions, depending on the target mRNAs that they regulate. miRNAs are transcribed as long premiRNA transcripts that, after processing, become mature miRNAs, which, through binding to partially complementary messenger RNAs, can regulate their stability and translational efficiency. miRNA genes are frequently found in small chromosomal alterations, but can also be dys-regulated by germ-line mutations or epigenetic modulation of their genomic loci. Earlier studies have shown that miRNA-101 is significantly down-regulated in several human HCC cell lines as well as in a set of HCCs, when compared to adjacent normal tissue. These reports also demonstrated that reexpression of miRNA-101 decreases the tumoregenicity of HCC cells in vitro and after xenotransplantation in vivo. Wang et al. started their analysis by purifying proteins that associate with enhancer of zeste 2 (EZH2) protein in HCC cells. EZH2 is widely expressed in a large set of human cancers and its overexpression is often correlated with advanced stage and poor prognosis. Biochemically, EZH2 acts as the catalytic core protein in polycomb repressor complex 2 (PRC2), which catalyzes the trimethylation of histone 3 lysine 27. EZH2 mediates gene silencing of genes that are involved in fundamental cellular processes, such as cell-fate decision, cell-cycle regulation, senescence, cell differentiation, and cancer. Importantly, EZH2 is itself regulated by miRNA-101, and loss of miRNA101 has been shown to result in overexpression of EZH2. Thus, miRNA-101 acts as a tumor suppressor by regulating the expression of EZH2. Using EZH2 in immunoprecipitation experiments, Wang et al. now show that another important regulator of liver cancer formation, the c-myc protein, can bind to EZH2, suggesting that EZH2 and c-myc cooperate in repressing miRNA-101 expression. Myc has long been established as an oncogene of central importance for the development of HCCs. Work by Felsher et al. showed that HCC generated in mice become addicted to this oncogene, because ablation of myc in preestablished tumors lead to complete regression. A central function of myc, which is critical for its ability to induce tumor formation, is the regulation of miRNAs. The c-myc oncogene is repressing and inducing the expression of several miRNAs. For example, through activation of the mir 17 cluster, c-myc can suppress apoptosis and DNA damage by regulating Abbreviations: EZH2, enhancer of zeste 2; HCC, hepatocellular carcinoma; miRNA-101, microRNA-101; PRC2, polycomb repressor complex 2. Address reprint requests to: Nisar P. Malek, M.D., Department of Internal Medicine I, Eberhard Karls University T€ ubingen, Otfried-M€ uller-Straß e 10, 72076 T€ ubingen, Germany. E-mail: Nisar.Malek@med.uni-tuebingen.de; fax: 01149-07071-292095. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26784 Potential conflict of interest: Nothing to report.