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Review
. 2017 Aug 8;24(1):53.
doi: 10.1186/s12929-017-0358-4.

Long non-coding RNA and tumor hypoxia: new players ushered toward an old arena

Jing-Wen Shih  1   2   3 , Hsing-Jien Kung  4   5   6   7
Affiliations
Review

Long non-coding RNA and tumor hypoxia: new players ushered toward an old arena (VSports手机版)

Jing-Wen Shih et al. J Biomed Sci. .

"V体育安卓版" Abstract

Hypoxia is a classic feature of the tumor microenvironment with a profound impact on cancer progression and therapeutic response. Activation of complex hypoxia pathways orchestrated by the transcription factor HIF (hypoxia-inducible factor) contributes to aggressive phenotypes and metastasis in numerous cancers. Over the past few decades, exponentially growing research indicated the importance of the non-coding genome in hypoxic tumor regions. Recently, key roles of long non coding RNAs (lncRNAs) in hypoxia-driven cancer progression have begun to emerge VSports手机版. These hypoxia-responsive lncRNAs (HRLs) play pivotal roles in regulating hypoxic gene expression at chromatic, transcriptional, and post-transcriptional levels by acting as effectors of the indirect response to HIF or direct modulators of the HIF-transcriptional cascade. Notably, the aberrant expression of HRLs significantly correlates with poor outcomes in cancer patients, showing promise for future utility as a tumor marker or therapeutic target. Here we address the latest advances made toward understanding the functional relevance of HRLs, the involvement of these transcripts in hypoxia response and the underlying action mechanisms, highlighting their specific roles in HIF-1 signaling regulation and hypoxia-associated malignant transformation. .

Keywords: Cancer; HIF-1α; HRL; Hypoxia; Hypoxia-responsive lncRNAs; Long non-coding RNA; Metastasis; lncRNA V体育安卓版. .

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The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
HIF (Hypoxia-inducible factor) activates its downstream target gene transcription in response to hypoxia. Under normoxia, (blue arrows), HIF-1α subunits are subjected to hydroxylation by PHDs (prolyl hydroxylase domain proteins) and other prolyl hydroxylases. Hydroxylated HIF-1α subunits are recognized by VHL (von Hippel–Lindau) proteins that target HIF-1α for subsequent ubiquitination and proteasomal degradation. During hypoxia (red arrows), the hydroxylation reactions are diminished, resulting in HIF-1α accumulation, dimerization with HIF-1β, binding to target genes and activation of target genes through recruitment of p300 and formation of the transcription initiation complex
Fig. 2
Fig. 2
Mechanisms of hypoxia-reponsive lncRNAs affecting HIF-1α activity. a Transcriptional activator. lncRNA ENST00000480739 suppresses HIF-1α expression by upregulating OS-9 transcription. OS-9 is a HIF-1α-binding protein that facilitates HIF-1α hydroxylation and proteasomal degradation. Another lncRNA RERT-lncRNA decreases the HIF-1α levels by upregulation of EGLN2 mRNA. EGLN2 encodes prolyl hydroxylase PHD1, which is responsible for HIF-1α hydroxylation and promoting HIF-1α degradation. b Transcriptional co-activator. LncHIFCAR acts as an oncogenic HIF-1α co-activator through direct binding to HIF-1α, thereby facilitating the recruitment of HIF-1α and p300 cofactor to the target promoters and stimulating HIF-1 target gene expression. c mRNA stability control. lncRNA-LET interacts with RNA-binding protein NF90, which has been implicated in the stabilization of target mRNAs. As the association between lncRNA-LET and NF90 could enhance the degradation of NF90, the hypoxia-induced downregulation of lncRNA-LET may thereby increase HIF-1A mRNA stability under hypoxic conditions. In addition, lncRNA HIF1A-AS2, an antisense transcripts transcribed from the 3′-UTR of the sense HIF1A mRNA negatively regulates HIF1A mRNA expression. Through base-pair binding to the HIF-1A mRNA 3′-UTR, HIF1A-AS2 could expose AU-rich elements within the HIF-1A mRNA 3′-UTR, thereby destabilizing of HIF-1A mRNA. d miRNA sponge/ceRNA. miR-145 negatively regulates expression of p70S6K1, a protein kinase responsible for promoting protein synthesis. Hypoxia-induced lincRNA-ROR could upregulate HIF-1α expression by sequestering endogenous miR-145. In addition to lincRNA-ROR, PVT1 lncRNAs upregulate HIF-1α expression by sponging miR-186. e Interaction decoy. lincRNA-p21 is capable of binding to both VHL and HIF-1α, leading to disruption of VHL/HIF-1α interaction. f LINK-A recruits and activates BRK and LRRK2 to phosphorylates HIF-1α. These phosphorylation modifications prevents HIF-1α degradation under normoxia and facilitates the interaction between HIF-1α and cofactor p300, thereby activating HIF-1 target genes. See text for detailed discussion
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