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normal tissue from effects of hypoxia (Brat et al. 2004 ). Hypoxia and the activation
of hypoxia response genes are thought to play a vital role in GBM progression, pro-
liferation, aggressiveness and resistance to therapy. This was directly demonstrated
in a recent multicenter trial that found hypoxia levels in GBM patients demonstrated
by^18 F–FMISO PET/CT correlated with worse prognosis (Gerstner et al. 2016 ).
The effect of hypoxia on cells is mediated through intracellular family of pro-
teins called hypoxia inducible factors (HIFs) which form transcriptional complexes
consisting of HIF-β subunit (ARNT- aryl hydrocarbon nuclear translocator) which
is constitutively expressed and oxygen regulated HIF-α subunits which belong to
the basic helix-loop-helix-Per-Arnt-Sims (PAS) family of transcriptional activators.
HIF1α (ubiquitously expressed), HIF 2α and HIF3α (tissue specific expression) are
the three mammalian HIF-1 subunits. Even though the HIF-1α is highly transcribed
and translated in normoxic conditions, it is rapidly hydroxylated on two conserved
proline residues (P402 and P564) on the oxygen dependent degradation domain
(ODD) by HIF specific prolyl hydroxylases PHD1, PHD2 and PHD3. Hydroxylated
HIF-1α is then recognized by the von Hippel-Lindau tumor suppressor (pVHL), a
subunit of E3 ubiquitin ligase which ubiquitinates HIF-1α for degradation by 26S
proteosome (Nath and Szabo 2012 ).
Under hypoxic conditions, the hydroxylation of ODD of HIF-1α and its subse-
quent recognition by pVHL is inhibited, resulting in the accumulation of HIF-1α
protein within the cytoplasm. In such conditions, HIF-1α translocated into the
nucleus and dimerizes with HIF-1β to form HIF-1α/β dimer complex. HIF-1α/β
dimer binds to HIF response elements (HRE) which contain the core consensus
sequence 5’RCGTG-3′ (R = purine residue) along with coactivators p300 and
CBP. HREs are present within promoters, introns and 3′ enhanced regions of many
stress response gene families which facilitate adaptations to hypoxic conditions
such as angiogenesis, hematopoietic growth factors, glucose transporters and glyco-
lytic enzymes thereby affecting cell proliferation, survival and movement (Nath and
Szabo 2012 ; Semenza 2010 , 2013 ).
HIF-1α levels also increase due to metabolic and genetic changes within tumors
such as increased production of H 2 O 2 (which stabilizes HIF-1α). Increase in the
levels of HIF-1α in response to low oxygen pressure leads to reprogramming of
tumor metabolism towards glycolysis, thereby increasing the expression of glucose
uptake receptors, glycolytic enzymes, lactate productions and reducing conversion
of pyruvate to acetyl coenzyme A. HIF-1α also increases the conversion of glucose
to glycogen by activating expression of hexokinases (HK1 and HK2), glycogen
synthase (GYS1), UDP- glucose pyrophosphorylase (UGP2), phosphoglucomutase
1 (PGM1), glycogen branching enzyme (GBE1) and PPP1R3C. PPP1R3C activates
GYS1 and also inhibits expression of liver-type glycogen phosphorylase (PYGL)
which breaks down glycogen. The reduced oxygen availability in GBM results in
increased oxidative phosphorylation and causes increased ROS generation, which
can lead to additional mutations. HIF-1α is increased through PI3K/AKT pathways
upon downregulation of PTEN. Additionally, PTEN mutations and its altered deg-
radation also increase HIF-1α levels within tumor cells (Fidoamore et al. 2016 ;
Nath and Szabo 2012 ; Semenza 2010 , 2013 ). HIF-1α is also thought to be involved
A. Sattiraju et al.