Summary Here we present a unifying hypothesis about how messenger RNAs, transcribed pseudogenes, and long non-coding RNAs “talk” to each other using microRNA response elements (MREs) as letters of a new language. We propose that this “competing endogenous RNA” (ceRNA) activity forms a large-scale regulatory network across the transcriptome, greatly expanding the functional genetic information in the human genome and playing important roles in pathological conditions, such as cancer.

Recent reports have described an intricate interplay among diverse RNA species, including protein-coding messenger RNAs and non-coding RNAs such as long non-coding RNAs, pseudogenes and circular RNAs. These RNA transcripts act as competing endogenous RNAs (ceRNAs) or natural microRNA sponges — they communicate with and co-regulate each other by competing for binding to shared microRNAs, a family of small non-coding RNAs that are important post-transcriptional regulators of gene expression. Understanding this novel RNA crosstalk will lead to significant insight into gene regulatory networks and have implications in human development and disease.

The importance of the physiological function of phosphatase and tensin homologue (PTEN) is illustrated by its frequent disruption in cancer. By suppressing the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity, PTEN governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture. Consequently, mechanisms regulating PTEN expression and function, including transcriptional regulation, post-transcriptional regulation by non-coding RNAs, post-translational modifications and protein-protein interactions, are all altered in cancer. The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus. Our increasing knowledge of PTEN and pathologies in which its function is altered will undoubtedly inform the rational design of novel therapies.

Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better understanding of the ‘metabolic switch’ in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a handful of metabolic pathways, while other pathways have remained in the dark. This Progress article brings to light the important contribution of fatty acid oxidation to cancer cell function.

SUMMARY Here we demonstrate that protein-coding RNA transcripts can crosstalk by competing for common microRNAs, with microRNA response elements as the foundation of this interaction. We have termed such RNA transcripts as competing endogenous RNAs (ceRNAs). We tested this hypothesis in the context of PTEN, a key tumor suppressor whose abundance determines critical outcomes in tumorigenesis. By a combined computational and experimental approach, we identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling and possess growth and tumor suppressive properties. Notably, we also show that these genes display concordant expression patterns with PTEN and copy number loss in cancers. Our study presents a road map for the prediction and validation of ceRNA activity and networks, and thus imparts a trans-regulatory function to protein-coding mRNAs.

Summary Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates required for biomass generation. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. Mechanistically, SIRT3 mediates metabolic reprogramming by destabilizing hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls glycolytic gene expression. SIRT3 loss increases reactive oxygen species production, leading to HIF1α stabilization. SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1α target genes. Finally, we find that SIRT3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression.

Stem cell function is an exquisitely regulated process. To date, however, the contribution of metabolic cues to stem cell function is poorly understood. Here we identify a novel PML - Peroxisome-proliferator activated receptor delta (PPARδ) - fatty acid oxidation (FAO) pathway for haematopoietic stem cell (HSC) maintenance. We have found that loss of Ppard profoundly affects the maintenance of HSCs. Moreover, treatment with PPARδ agonists improves these HSC functions, whereas, conversely, inhibition of mitochondrial FAO induces loss of the HSC compartment. Importantly, we demonstrate that PML exerts its essential role in HSC maintenance through regulation of PPAR signalling and FAO. Mechanistically, the PML-PPARδ-FAO pathway controls HSC asymmetric division. Depletion of Ppard or Pml, as well as FAO inhibition, results in symmetric commitment of HSC daughter cells while, conversely, PPARδ activation increases asymmetric division. Thus, our findings identify a new metabolic switch for the control of HSC cell fate with important therapeutic implications.

The cancer transcriptome is characterized by aberrant expression of both protein-coding and non-coding transcripts. Similar to mRNAs, a significant portion of the non-coding transcriptome including long non-coding RNAs and pseudogenes harbors microRNA-response elements. The recent discovery of competitive endogenous RNAs (ceRNA), natural decoys that compete for a common pool of microRNAs, provides a framework to systematically functionalize MRE-harboring non-coding RNAs and integrate them with the protein-coding RNA dimension in complex ceRNA networks. Functional interactions in ceRNA networks aid coordinating a number of biological processes and, when perturbed, contribute to disease pathogenesis. In this review, we discuss recent discoveries that implicate natural miRNA decoys in the development of cancer.