Abstract
Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.
Highlights
Activation of hypoxia pathways is a common feature of many types of cancer and frequently correlates with an aggressive tumor phenotype and adverse clinical outcome.[1]
We confirmed the binding of hypoxia-inducible factor (HIF)-1α, HIF-2α and HIF-1β at the binding site identified by the ChIP-seq experiments using ChIP-quantitative PCR (qPCR) (Figures 1f and h)
In addition to regulating the coding transcriptome, it is becoming apparent that hypoxic transcriptional pathways orchestrated by HIF control the expression of non-coding regulatory transcripts, long non-coding RNA (lncRNA).[5]
Summary
Activation of hypoxia pathways is a common feature of many types of cancer and frequently correlates with an aggressive tumor phenotype and adverse clinical outcome.[1]. A major mechanism mediating oxygen-dependent transcriptional responses is hypoxia-inducible factor (HIF). HIF is a family of heterodimeric transcription factors comprising a common, constitutive HIF-1β subunit and a regulated HIF-α subunit.[2] HIF-1 contains a HIF-1α subunit and HIF-2 contains a HIF-2α subunit each complexed with HIF-1β. HIF controls the expression of many hundreds of genes with important roles in oncogenic pathways including the regulation of proliferation, apoptosis, tumor metabolism, epithelial-to-mesenchymal transition, invasiveness and pH regulation.[3] To date, study has largely focused on the regulation of protein-coding genes by these pathways.[4] new sequencing technologies are identifying increasing numbers of non-coding transcripts with regulatory roles that are important in cancer biology.[5,6] Pangenomic studies have shown that many of these non-coding genes are regulated by hypoxia and that long non-coding RNAs (lncRNAs), in particular, are regulated by HIF transcriptional pathways.[5] In addition, several studies have demonstrated the regulation of specific lncRNAs in hypoxia, including H19,7 lncRNA-low expression in tumor,[8] lincRNA-p21,9 hypoxia-induced noncoding ultra-conserved transcripts,[10] Linc-RoR11 and urothelial carcinoma-associated 1 (UCA1)[12] many of which have important roles in cancer
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