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Gene & Protein in Disease Opportunities and challenges of HIF-1 in cancer

correlation between HIF-1 and different cancer features have implicated UCHL1 in tumorigenesis, metastasis, and
such as angiogenesis, metabolic reprogramming, invasion, invasiveness of cancers, providing a rationale for using it as
metastasis, and poor patient outcomes. Therefore, targeting a prognostic marker and treatment target for cancers. To do
HIF-1 and its upstream regulators is considered a valuable so, the following aspects must be taken into consideration:
strategy for cancer therapy. 73 the influence of UCHL1 on HIF-2α, the detection of
downstream substrates by UCHL1, the expression levels
Apart from hypoxia, different factors may influence
HIF-1 overexpression, including insulin, insulin-like of UCHL1 in normal tissues, and the impact of epigenetic
alterations.
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growth factor, v-Src, lactate, pyruvate, ROS levels, and
genetic alterations such as activation of oncogene signaling The abnormal expression of IDH3α, a subunit of
or inactivation of tumor suppressor genes. There is the IDH3 heterotetramer, has been shown to intensify
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growing evidence that numerous microRNAs are involved HIF-1 stability and activity, as opposed to the decrease of
in HIF-1-mediated regulation of the Warburg effect. α-ketoglutarate levels in cancer cells. On the other hand,
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One example is miR-31-5p, a microRNA upregulated in silencing of IDH3α interrupted the Warburg effect and
lung adenocarcinoma, which has been found to amplify angiogenesis, leading to significantly slower tumor growth.
the Warburg effect and encourage cell proliferation by In lung and breast cancer patients, IDH3α expression was
inhibiting FIH-1 and enhancing HIF-1 activity. Another associated with poor post-operative OS. 78
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example is miR-150, which is abnormally expressed in In vitro studies suggest that LY6E overexpression
various cancers. This microRNA targets and inhibits the enhanced the transcription of HIF-1, which subsequently
pVHL tumor suppressor gene, the E3 ligase responsible increases the expression of proangiogenic factors, VEGF
for HIF-1 degradation, in glioma cells. In the presence of and PDGFB. This effect occurs through the decreased
miR-150, HIF-1 is stabilized, leading to increased glucose levels of both endogenously and exogenously expressed
uptake, lactate production, and cell proliferation. 76 PTEN mRNA and activation of the PI3K/Akt pathway.
Specific genetic screening experiments have The expression levels of LY6E were significantly higher
identified several novel activators of HIF-1, including in human breast cancers in comparison with normal
ubiquitin C-terminal hydrolase-L1 (UCHL1), isocitrate breast tissues, contributing to poor prognoses in patients
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dehydrogenase 3α (IDH3α), and lymphocyte antigen with lung, bladder, brain, and skin cancers. These results
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6 locus E (LY6E). In vitro experiments have shown justify the use of LY6E as a prognostic marker as well as
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that UCHL1 stabilizes and stimulates HIF-1 through its a therapeutic target for cancers. Importantly, the basal
deubiquitination activity. 77 expression levels of LY6E were shown to be high in normal
T-cells, which should be carefully considered when
The expression levels of UCHL1 correlated well with developing LY6E-targeted cancer therapies. 80
those of HIF-1, and UCHL1 expression levels in tumors
were associated with poor prognosis in both breast and lung Histone deacetylase inhibitors (HDAIs) have shown
cancer patients. It is of note, however, that the influence of promising anticancer and antiangiogenic potential in
UCHL1 on HIF-1 expression was higher in clinical tumor clinical trials. HDAIs have been demonstrated to possess
tissues compared to cancer cells cultured under low- destabilizing and repressive effects on HIF-1 function,
oxygen conditions. The particular reason for this difference an essential pharmacological mechanism supporting
is currently unclear, but it is possible that other conditions their ability to suppress tumor growth and angiogenesis.
besides hypoxia, including glucose or oxygen deficiency, However, it must be taken into consideration that HDAIs
may influence the activity of the UCHL1–HIF-1 axis, as may cause significant adverse effects due to off-target
demonstrated by the in vitro experiments. Specifically, hyperacetylation. 79
under hypoxic conditions and decreased glucose Hypoxia-associated factor (HAF) is an E3 ligase that
concentrations, the impact of UCHL1 on HIF-1 stability regulates the stability and functionality of HIF-1. Elevated
was expedited. Following UCHL1 overexpression, HAF levels in tumor cells compared to normal cells
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quantitative analysis of intermediary metabolites showed under similar conditions demonstrate its effect on cancer
that these genes induced a switch in the glucose metabolic progression. In addition, HAF operates as a neoplastic
pathway from oxidative phosphorylation to aerobic antigen, also known as squamous cell carcinoma antigen
glycolysis. In parallel, the PPP was activated, allowing recognized by T-cells (SART1800), indicating tumor
increased production of NADPH and reduced GSH. The aggressiveness and poor prognosis. HAF has been
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elevated GSH levels due to an enhanced UHCL1 expression reported to bind to HIF-1 and trigger its degradation in an
promoted the radioresistance of cancer cells, according oxygen-independent manner. Although this action might
to in vitro colony formation assays. Numerous studies be expected to inhibit tumor proliferation and expansion, it
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Volume 3 Issue 2 (2024) 8 doi: 10.36922/gpd.3431