Enhancer RNA (eRNA) is a type of noncoding RNA transcribed from the enhancer. Although critical roles of eRNA in gene transcription control have been increasingly realized, the systemic landscape and potential function of eRNAs in cancer remains largely unexplored. Here, we report the integration of multi-omics and pharmacogenomics data across large-scale patient samples and cancer cell lines. We observe a cancer-/lineage-specificity of eRNAs, which may be largely driven by tissue-specific TFs. eRNAs are involved in multiple cancer signaling pathways through putatively regulating their target genes, including clinically actionable genes and immune checkpoints. They may also affect drug response by within-pathway or cross-pathway means. We characterize the oncogenic potential and therapeutic liability of one eRNA, NET1e, supporting the clinical feasibility of eRNA-targeted therapy. We identify a panel of clinically relevant eRNAs and developed a user-friendly data portal. Our study reveals the transcriptional landscape and clinical utility of eRNAs in cancer.

No abstract

SUMMARY Autophagy defects have been recently associated with chromosomal instability (CIN), a hallmark of human cancer. However, the functional specificity and mechanism of action of autophagy-related factors in genome stability remain elusive. Here we report that UVRAG, an autophagic tumor suppressor, plays a dual role in chromosomal stability, surprisingly independent of autophagy. We establish that UVRAG promotes DNA double-strand-breaks repair by directly binding and activating DNA-PK in non-homologous end-joining. Disruption of UVRAG increases genetic instability and sensitivity of cells to irradiation. Furthermore, UVRAG was found also localized at centrosomes and physically associated with CEP63, an integral component of centrosomes. Disruption of the association of UVRAG with centrosomes causes centrosome instability and aneuploidy. UVRAG thus represents an autophagy-related molecular factor that also has a convergent role in patrolling both the structural integrity and proper segregation of chromosomes, which may confer autophagy-independent tumor suppressor activity.

Enhancers are distal genomic elements critical for gene regulation and cell identify control during development and diseases. Many human cancers were found to associate with enhancer malfunction, due to genetic and epigenetic alterations, which in some cases directly drive tumour growth. Conventionally, enhancers are known to provide DNA binding motifs to recruit transcription factors (TFs) and to control target genes. However, recent progress found that most, if not all, active enhancers pervasively transcribe noncoding RNAs that are referred to as enhancer RNAs (eRNAs). Increasing evidence points to functional roles of at least a subset of eRNAs in gene regulation in both normal and cancer cells, adding new insights into the action mechanisms of enhancers. eRNA expression was observed to be widespread but also specific to tumour types and individual patients, serving as opportunities to exploit them as potential diagnosis markers or therapeutic targets. In this review, we discuss the brief history of eRNA research, their functional mechanisms and importance in cancer gene regulation, as well as their therapeutic and diagnostic values in cancer. We propose that further studies of eRNAs in cancer will offer a promising 'eRNA targeted therapy' for human cancer intervention.