Abstract
Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.
Highlights
Hypoxic conditions are a challenge for oxygen-dependent mammalian cells requiring an adequate cellular response in order to adapt metabolic and proliferative processes
During normoxic conditions, Hypoxia-inducible factor (HIF)-1α and HIF-2α are constantly degraded through initial hydroxylation by prolyl hydroxylase (PHD) enzymes which further enables binding to the von Hippel-Lindau (VHL) protein [3,4]
This significantly impacts tumor growth and progression as, for instance, HIF overexpression promotes cancer angiogenesis or activates glycolysis in addition to the aerobic metabolism compensating for the increased energy demands of fast proliferating cancer cells, which is known as the Warburg effect [12,13]
Summary
Hypoxic conditions are a challenge for oxygen-dependent mammalian cells requiring an adequate cellular response in order to adapt metabolic and proliferative processes. Under hypoxic conditions, PHDs are no longer active, leading to HIFα accumulation and further dimerization with the HIF-1β subunit This enables binding to hypoxia response elements (HRE) in the promoter regions of target genes, which aims to reduce cellular oxygen consumption by, for instance, activating anaerobic glycolysis or promoting angiogenesis [1,5]. HIFs may be upregulated in normoxia [9,10,11] This significantly impacts tumor growth and progression as, for instance, HIF overexpression promotes cancer angiogenesis or activates glycolysis in addition to the aerobic metabolism compensating for the increased energy demands of fast proliferating cancer cells, which is known as the Warburg effect [12,13]. HIFs represent a powerful potential therapeutic target which is being investigated in several clinical trials aiming to therapeutically target HIFs [16,17]
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