Hypoxia in the Cell Cycle
The cell cycle is an important cellular process whereby the cell attempts to replicate its genome in an error-free manner.
The cell cycle is a process through which cells faithfully replicate their genetic material. Strict control over its progression is therefore needed to avoid errors that could result in cell death or cell malignancy. As such, understanding how the cell cycle is affected by external and internal stresses is of the utmost importance, in particular, the stress caused by hypoxia, or reduced oxygen availability. Hypoxia is an important factor in embryo development but is also present in numerous pathological settings such as ischaemic events and cancer . Oxygen is fundamental for both energy homeostasis and cellular viability, therefore, to deal with such stresses, cells possess complex response mechanisms that aim at restoring oxygen homeostasis.
2. Hypoxia Signalling Pathway
3. Cell Cycle Overview
4. Hypoxia Mediated Transcriptional Effects on Cell Cycle Components
Hypoxia plays a central role in diverse aspects of cancer biology as a hypoxic microenvironment is prevalent in solid tumours. It is known that oxygen levels regulate cell proliferation and that depending on the cell type, hypoxia can inhibit cell proliferation by inducing cell cycle arrest [15,16,17]. However, tumour cells often adapt to survive in such hypoxic conditions. This adaptation is partially promoted by the essential role HIF plays in the transcriptional regulation of genes associated with angiogenesis, apoptosis, cell proliferation, and energy metabolism . HIF-dependent activation of these genes provides tumour cells with an adaptive advantage over normal cells during periods of hypoxic stress.
The Myc transcription factor, which is also associated with cell proliferation, is similarly overexpressed in various cancer types . Myc is known to repress the expression of the CDK cyclin inhibitors p21 and p27 . In hypoxia, the expression of p21 and p27 is induced in a HIF-1α dependent manner, partially by displacing Myc from their promoters . Interestingly, HIF-2α cooperates with Myc and promotes cell proliferation in renal clear cell carcinomas (RCC) and other cell types . In RCC, HIF-2α is also known to induce Cyclin D1 via its binding to an enhancer site  (Figure 3). The effects of HIF-2α on cell cycle control in RCC cells have become even clearer following data derived from treatments with a specific HIF-2α inhibitor (PT2399), in which the cell cycle was identified as the main signature controlled by HIF-2α [21,22].
The mitotic kinase—Aurora A (AURKA)—also has an important role in mitotic progression and has been related to oncogenic phenotypes . AURKA is overexpressed in a variety of different tumours and has been implicated in cell transformation and centrosome amplification [24,25]. In hepatocellular carcinomas (HCC), the increased levels of AURKA do not always correlate with gene amplification . Interestingly, AURKA was shown to be induced by hypoxia in a HIF-1α dependent manner in HepG2 cells  as HIF-1α binds to the AURKA promoter and upregulates its transcription, leading to an increase in cell proliferation . This study proposed that AURKA might be involved in the hypoxia-induced proliferation of HCC tumours  (Figure 3). In this tumour type, hypoxia induction of HIF-1α and AURKA might be involved in promoting HCC proliferation . However, in breast cancer cells (MCF-7, MDA-MB-231, and SK-Br3), microarray analysis in response to hypoxia illustrates that hypoxia downregulates AURKA . In this study, the authors demonstrated that hypoxia downregulated AURKA via a HIF-1α dependent mechanism, suggesting that HIF-1α is a negative regulator of AURKA in breast cancer tumours . These studies highlight the cell-specific nature of HIF’s function in cell cycle regulation.
Cell division cycle-associated protein 2 (CDCA2) has similarly been shown to be a target of the hypoxia pathway . Analyses of publicly available ChIP-Seq and RNA-Seq datasets demonstrate that CDCA2 is induced in hypoxia and is important for the control of proliferation in prostate cancer cells. The intracellular signal transducer protein, SMAD3, binds to the CDCA2 promoter and recruits HIF-1α. HIF-1α/SMAD3 then mediates the transcriptional regulation of CDCA2 in hypoxic tumours, leading to cancer cell proliferation .
Among all known hypoxia-stimulated transcription factors, the importance of NF-κB has been identified in a wide range of signalling systems, alongside its association with many different diseases. In contrast to its well-established role in immune and inflammatory responses, NF-κB activity is also involved in apoptosis, carcinogenic transformation, and cell cycle transition . The NF-κB family consists of five distinct members, which include RelA (p65), RelB, c-Rel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52), all of which share a conserved Rel homology domain . Hypoxia activation of NF-κB occurs via several mechanisms, although some of the details still require further investigation. Hypoxia has been shown to control NF-κB via the action of PHDs and FIH [32,33,34], and requires the involvement of calcium/calmodulin-dependent kinase II (CAMKII), transforming growth factor kinase 1 (TAK1) and IκB kinase (IKK) [35,36,37].
NF-κB has several target genes identified with a role in cell cycle progression (reviewed in detail ). Ultimately, cyclin D1 provides a predominant link between NF-κB and cell cycle progression (Figure 3). Cyclin D1, in association with CDK4 and CDK6, promotes G1/S phase transition through CDK-dependent phosphorylation of retinoblastoma protein (pRB) . This phosphorylation event releases the transcription factor E2F, which is required for the activation of S-phase-specific genes, although several studies have conversely reported that NF-κB can itself induce cell cycle arrest . Overexpression of RelA has been shown to arrest cells at G1/S-phase transition . c-Rel overexpression leads to cell cycle arrest through p53 protein stabilization, an important upstream activator of the CDK-inhibitor, p21 . Additionally, p21 expression can be further increased by the Formin-2 (FMN2) protein, which is a component in the p14ARF tumour suppressor pathway . In this study, FMN2 was shown to increase with hypoxia stimulation via an NF-κB-dependent mechanism . Moreover, several additional studies have shown that NF-κB can be activated by a hypoxic environment [35,36,43,44].
Finally, a physical and functional interaction exists between the IKK/NF-κB signalling pathway and the cell cycle regulatory proteins of the E2F family that controls S-phase entry, which suggests that NF-κB plays a functional role in controlling cell division [45,46]. Indeed, direct phosphorylation of E2F by IKKα and IKKβ resulted in the nuclear accumulation and enhanced DNA binding of the E2F4/p130 repressor complex, which led to the suppression of E2F-responsive gene expression . In contrast, E2F1 and NF-κB interactions were shown to control the timing of cell proliferation  (Figure 3). Despite all of these links between NF-κB and cell cycle regulation, a more systematic and mechanistic analysis of how NF-κB controls the cell cycle in hypoxia is needed.
The entry is from 10.3390/ijms22094874
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