Hypoxia-Induced Non-Coding RNAs Controlling Cell Viability in Cancer

Abstract

Hypoxia, a characteristic of the tumour microenvironment, plays a crucial role in cancer progression and therapeutic response. The hypoxia-inducible factors (HIF-1α, HIF-2α, and HIF-3α), are the master regulators in response to low oxygen partial pressure, modulating hypoxic gene expression and signalling transduction pathways. HIFs' activation is sufficient to change the cell phenotype at multiple levels, by modulating several biological activities from metabolism to the cell cycle and providing the cell with new characteristics that make it more aggressive. In the past few decades, growing numbers of studies have revealed the importance of non-coding RNAs (ncRNAs) as molecular mediators in the establishment of hypoxic response, playing important roles in regulating hypoxic gene expression at the transcriptional, post-transcriptional, translational, and posttranslational levels. Here, we review recent findings on the different roles of hypoxia-induced ncRNAs in cancer focusing on the data that revealed their involvement in tumour growth.

Keywords: HIF; cancer; cell cycle; hypoxia; lncRNAs; miRNAs; proliferation.

Figure 1

Hypoxia-inducible factor (HIF) complex transcriptionally activates non-coding RNAs (ncRNAs) in response to hypoxia. Under normoxia (black arrows), HIF-1/2α subunits are subjected to hydroxylation by prolyl hydroxylase domain enzymes (PHDs) and other prolyl hydroxylases. Hydroxylated HIF-1/2α subunits are recognized by VHL proteins and targeted for subsequent ubiquitination and proteasomal degradation. Under hypoxia (red arrows), low pO₂ results in HIF-1/2α accumulation, nuclear translocation and dimerization with HIF-b, finally, after recruitment of CBP/p300, the transcription initiation complex binds the promoter of target genes inducing their expression. Among the hypoxia-induced RNAs, the ncRNAs (miRNAs or lncRNAs) will be involved in different pathways, regulating cell proliferation, cell cycle and cell death. Moreover, some of these can regulate HIF itself.

Figure 2

Direct or indirect feedback loops between HIF-1α and hypoxia-regulated ncRNAs. The hypoxia-regulated ncRNAs, HIF-1α, and other co-operators intertwine to form reciprocal feedback loops in both positive and negative manners, represented in the figure respectively with red arrows and blue lines. (A) Reciprocal feedback loops between HIF-1α and hypoxia-regulated lncRNAs. (B) Reciprocal feedback loops between HIF-1α and hypoxia-regulated miRNAs.