Oxygen is crucial for an organism to stay alive and the lack of sufficient oxygen is interpreted as an extreme stress condition. Adaptation to hypoxic conditions is a significant property of tumor cells which have evolved mechanisms to survive under this extreme stress condition. The master regulator of adaptation to low oxygen levels is a heterodimer protein called HIF1, which is differentially activated according to oxygen availability in the cellular environment.
Mammalian cells require a certain level of oxygen in the environment in order to maintain homeostasis and to carry out aerobic respiration. However, in cancer and some other cardiovascular and pulmonary diseases, the cellular oxygen balance significantly changes in a way that pushes cells to survive under hypoxic conditions . Survival under hypoxic conditions that arise from the insufficient delivery of oxygen via blood vessels to the rapidly growing tumor mass is a common feature of cancerous cells . Cells that experience hypoxia develop adaptation to low-oxygen levels by activating cellular pathways related to cell survival, proliferation and metabolism. The ability of cancer cells to adapt to hypoxic conditions has been linked to tumor malignancy, resistance/unresponsiveness to treatment and poor prognosis .
The master regulator of adaptation to hypoxia is a transcription factor called HIF-1 (Hypoxia-Inducible Factor-1) [4,5]. HIF1 is a heterodimer protein that is composed of HIF1- and HIF1- subunits. HIF1- and its analogs HIF2- and HIF3- have N-terminal and C-terminal transactivation domains (TADs) (Figure 1). C-TAD domain acts in regulation of gene activity by interacting with transcriptional regulators such as CBP/p300. On the other hand, N-TAD helps stabilize HIF1- and protects it from proteosomal degradation [6,7]. In contrast to the constitutively active HIF1- subunit, the expression of HIF1- subunit depends on the oxygen levels present in the environment. Under normal oxygen levels (normoxia), HIF1- undergoes proline hydroxylation by FIH (factor inhibiting HIF) enzyme, which then targets it for the ubiquitin ligase complex and leads to proteosomal degradation . Under insufficient oxygen levels (hypoxia), FIH gets inactivated which in turn inhibits targeting HIF1- for proteosomal degradation. As HIF1- stabilizes and accumulates, it translocates to the nucleus where it joins with the subunit to form the HIF1 heterodimer .
Functional HIF1 heterodimer regulates more than a hundred genes by binding to the HRE (hypoxia responsive element) domains encompassing 5-[AG]CGTG-3 sequence , (Figure 2). Transcriptional coactivators such as CREBBP and CBP/p300 also contribute to the gene activation regulated by HIF1 under hypoxic conditions. HIF1 target genes are involved in several important cellular processes such as energy metabolism, glucose metabolism, angiogenesis, apoptosis and proliferation (Table 1). Therefore, HIF1 mediated regulation is considered a key regulator of embryonic vascularization, tumor angiogenesis and the pathophysiology of ischemic diseases. The transcriptional regulation of p53 which plays a significant role in cellular adaptation to genotoxic stress is carried out in a similar manner to that of HIF1-‘s. p53 is an important tumor
suppressor protein that is involved in DNA damage, cell cycle
control, apoptosis and senescence. Although it is expressed at
low levels under normal conditions, upon DNA damage it gets
phosphorylated and stabilized, which then provides target gene
regulation [11, 12].
In addition, under hypoxic conditions p53 regulates a
different set of target genes using a different mechanism than
the DNA damage pathway. Previous studies indicate that there
is a cross-regulation at the transcriptional level between
HIF1 and p53 which are two important players in developing
cellular adaptation to various stress conditions . This crossregulation
can either be activating or repressing depending on
several other factors. Furthermore, under hypoxic conditions
HIF1 and p53 compete to bind p300 which is required for the
transcriptional activation of them both . The fact that p300
and PCAF (p300/CBP Associated Factor) which is the other
transcriptional co-activator that participates in this regulation
possess histone acetyltransferase (HAT) property hints towards
epigenetic regulation in developing cellular adaptation to
Cellular adaptation to low oxygen levels involves a complex
regulatory mechanism that allows the cells to maintain their
homeostasis and survive. The interplay between HIF1, the
master regulator of the response to hypoxia, and one of the most
important tumor suppressors p53 is very important for cancer
cells to gain the ability to thrive under hypoxic conditions. This
interaction between HIF1 and p53 also points at the significance
of transcriptional co-activators such as CBP/p300, both at the
level of target gene regulation and their roles in modulating
chromatin as histone acety transferases. Further studies
towards HIF1, p53 and the epigenetic regulation between them
will enable researchers to have a better understanding of cancer
cell survival under hypoxia.