Long Noncoding RNA: “LNCs” to Cancer

Abstract

In recent years we have witnessed a paradigm shift concerning the long-lasting controversy over ‘‘junk DNA’’ in the human genome. It is now well established that, besides the roughly 25 000 protein-coding genes, the genome contains tens of thousands of functional elements. In addition, the completion of the ENCODE project—the functional annotation of all regulatory regions of the human genome—has confirmed that 80% of genome is transcribed into RNA, whereas <than 2% is translated into proteins. Thus, an as yet unknown number of transcripts lacking significant coding potential, including long noncoding RNAs (lncRNAs), exceed the number of protein-coding genes [1]. However, the expression, regulation, sequence, function, andmechanism of action of the vastmajority of lncRNAs are currently largely unknown. For the few lncRNAs that are characterized at the functional level, evidence is accumulating that they play important roles in malignant diseases: All hallmarks of cancer thatdefine themalignantphenotypeof tumorcellsare controlled by one or another lncRNA [2]: LncRNAs contribute toward sustaining proliferative signaling, evading growth suppression, resisting apoptosis, enabling replicative immortality, activating invasion and metastasis, and inducing angiogenesis in a large variety of tumor entities. The lncRNA HOX transcript antisense RNA (HOTAIR), for example, promotes breast cancer metastasis by binding to polycomb repressive complex 2 (PRC2), thereby inhibiting gene expression [3]. The lncRNA X inactive specific transcript (XIST) is a central player in X chromosome inactivation during embryonal development but also acts as a tumor suppressor in myeloproliferative neoplasms [4]. The lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is a key