Molecular Crosstalk Between MYC and HIF in Cancer

Li, Yanping; Sun, Xiao Xin; Qian, David Z.; Dai, Mu Shui

doi:10.3389/fcell.2020.590576

Cited by 56 publications

(53 citation statements)

References 143 publications

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“…All of the aforementioned pathways and molecules have crosstalk with the master regulator and oxygen-sensing transcription factor HIF-1 [ 11 ]. Some examples include the activation of regulatory subunit HIF-1α by Akt and mTOR [ 12 ], the inhibition of Myc by HIF under hypoxic conditions and cooperation between the two molecules to promote cancer cell growth [ 13 ], and the inhibition of HIF-1α via high p53 expression [ 14 ]. This molecular crosstalk is especially important because HIF-1 exerts major effects on glucose metabolism when active.…”

Section: Glucose Metabolism and The Warburg Effect: A Century Latermentioning

confidence: 99%

Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

Schiliro

Firestein

2021

Cells

290

152

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Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.

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Section: Glucose Metabolism and The Warburg Effect: A Century Latermentioning

confidence: 99%

Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

Schiliro

Firestein

2021

Cells

290

152

View full text Add to dashboard Cite

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“…The stress-responsive genetic regulator Sirtuin1, which has been shown to have an influence on the stability of HIF-1α expression has also been associated with the regulation of NMYC expression [ 36 , 37 , 38 , 39 ]. In its role as a stabilizer of HIF-1α and HIF-2α expression, it might be hypothezised to be able to contribute to activation of AQP1 in a hypoxia-dependent manner [ 38 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

AQP1-Driven Migration Is Independent of Other Known Adverse Factors but Requires a Hypoxic Undifferentiated Cell Profile in Neuroblastoma

et al. 2021

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Neuroblastoma is a biologically very heterogeneous tumor with its clinical manifestation ranging from spontaneous regression to highly aggressive metastatic disease. Several adverse factors have been linked to oncogenesis, tumor progression and metastases of neuroblastoma including NMYC amplification, the neural adhesion molecule NCAM, as well as CXCR4 as a promoter of metastases. In this study, we investigate to what extent the expression of AQP1 in neuroblastoma correlates with changing cellular factors such as the hypoxic status, differentiation, expression of known adverse factors such as NMYC and NCAM, and CXCR4-related metastatic spread. Our results show that while AQP1 expression leads to an increased migratory behavior of neuroblastoma cells under hypoxic conditions, we find that hypoxia is associated with a reduction of NMYC in the same cells. A similar effect can be observed when using the tetracycline driven mechanism of SH-EP/Tet cells. When NMYC is not expressed, the expression of AQP1 is increased together with an increased expression of HIF-1α and HIF-2α. We furthermore show that when growing cells in different cell densities, they express AQP1, HIF-1α, HIF-2α, NMYC and NCAM to different degrees. AQP1 expression correlates with a hypoxic profile of these cells with increased HIF-1α and HIF-2α expression, as well as with NMYC and NCAM expression in two out of three neuroblastoma cell lines. When investigating cell properties of the cells that actually migrate, we find that the increased APQ1 expression in the migrated cells correlates with an increased NMYC and NCAM expression again in two out of three cell lines. Expression of the tumor cell homing marker CXCR4 varies between different tumor areas and between cell lines. While some migrated tumor cells highly express CXCR4, cells of other origin do not. In the initial phase of migration, we determined a dominant role of AQP1 expression of migrating cells in the scratch assay.

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“…In particular, glutaminase, a key enzyme converting glutamine to glutamate, was found to be increased in several cell types, including osteoblasts [ 84 ] and, via HIF-1, in colorectal cancer cells, which required glutaminase for hypoxia-induced migration and invasion in vitro, and tumour growth and metastatic colonisation in vivo [ 85 ]. The relationship between Myc and HIF is complex [ 86 ]. It has been shown that HIF-1α and HIF-2α have opposing effects on Myc; HIF-1α decreased Myc expression [ 87 ] while HIF-2α promoted c-Myc activity in various cell types [ 88 ].…”

Section: Glutamine Metabolism and Hypoxiamentioning

confidence: 99%

HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells

Lee

Golinska

Griffiths

2021

Cells

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In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.

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Molecular Crosstalk Between MYC and HIF in Cancer

Cited by 56 publications

References 143 publications

Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

AQP1-Driven Migration Is Independent of Other Known Adverse Factors but Requires a Hypoxic Undifferentiated Cell Profile in Neuroblastoma

HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells

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