The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of numerous lncRNAs in cancer is known to contribute to virtually all hallmarks of cancer. An important regulatory mechanism of lncRNAs is the post-transcriptional regulation mediated by RNA-binding proteins (RBPs). So far, however, only a small number of known cancer-associated lncRNAs have been found to be regulated by the interaction with RBPs like human antigen R (HuR), ARE/poly(U)-binding/degradation factor 1 (AUF1), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and tristetraprolin (TTP). These RBPs regulate, by various means, two aspects in particular, namely the stability and the localization of lncRNAs. Importantly, these RBPs themselves are commonly deregulated in cancer and might thus play a major role in the deregulation of cancer-related lncRNAs. There are, however, still many open questions, for example regarding the context specificity of these regulatory mechanisms that, in part, is based on the synergistic or competitive interaction between different RBPs. There is also a lack of knowledge on how RBPs facilitate the transport of lncRNAs between different cellular compartments. Compared to protein-coding genes, lncRNAs are poorly conserved between different species and their expression levels are rather low [7,8]. Initially, this led to the belief that they were nothing but transcriptional noise [6][7][8]. Soon, however, it was discovered that lncRNAs do exhibit considerable functionality, for example as regulators of transcription [6][7][8]. Mechanisms of transcriptional regulation by lncRNAs are multifarious and can occur either in cis or in trans, meaning either closer to or further away from the lncRNA's site of transcription, respectively [6,7]. A frequent mechanism of transcriptional regulation via lncRNAs is the recruitment, or prevention of such, of components of chromatin or histone-modifying complexes, like polycomb repressive complexes or histone deacetylase complexes [11][12][13]. LncRNAs can also direct transcription factors or cofactors to promoter regions of genes and facilitate the formation of chromatin loops between distant enhancers and promoters, as observed for some eRNAs [9,[14][15][16][17]. Another way that they can impact transcription is by interfering with the RNA polymerase II transcription machinery, thereby blocking transcriptional initiation or elongation [18]. LncRNAs are important regulators not only at the level of transcription but also at the post-transcriptional level [6,7]. They regulate pre-mRNA splicing by interacting with splicing factors or with the mRNA itself [19][20][21][22]. A well-studied example for this is metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an lncRNA that interacts with serine/arginine (SR) spl...

Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.

Long non-coding RNAs (lncRNAs) are defined as non-protein coding transcripts with a minimal length of 200 nucleotides. They are involved in various biological processes such as cell differentiation, apoptosis, as well as in pathophysiological processes. Numerous studies considered that frequently deregulated lncRNAs contribute to all hallmarks of cancer including metastasis, drug resistance, and angiogenesis. Angiogenesis, the formation of new blood vessels, is crucial for a tumor to receive sufficient amounts of nutrients and oxygen and therefore, to grow and exceed in its size over the diameter of 2 mm. In this review, the regulatory mechanisms of lncRNAs are described, which influence tumor angiogenesis by directly or indirectly regulating oncogenic pathways, interacting with other transcripts such as microRNAs (miRNAs) or modulating the tumor microenvironment. Further, angiogenic lncRNAs occurring in several cancer types such as liver, gastrointestinal cancer, or brain tumors are summarized. Growing evidence on the influence of lncRNAs on tumor angiogenesis verified these transcripts as potential predictive or diagnostic biomarkers or therapeutic targets of anti-angiogenesis treatment. However, there are many unsolved questions left which are pointed out in this review, hence driving comprehensive research in this area is necessary to enable an effective use of lncRNAs as either therapeutic molecules or diagnostic targets in cancer.

The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA NEAT1 as a molecular trigger for ALYREF effects in breast cancer. Mechanistically, we found that ALYREF binds to the NEAT1 promoter region to enhance the global NEAT1 transcriptional activity. Importantly, by stabilizing CPSF6, a protein that selectively activates the post-transcriptional generation of the short isoform of NEAT1, as well as by direct binding and stabilization of the short isoform of NEAT1, ALYREF selectively fine-tunes the expression of the short NEAT1 isoform. Overall, our study describes ALYREF as a novel factor contributing to breast carcinogenesis and identifies novel molecular mechanisms of regulation the two isoforms of NEAT1.