HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis

Meléndez-Rodríguez, Florinda; Urrutia, Andrés; Lorendeau, Doriane; Rinaldi, Gianmarco; Roche, Olga; Böğürcü-Seidel, Nuray; Muelas, Marta Ortega; Mesa-Ciller, Claudia; Turiel, Guillermo; Bouthelier, Antonio; Hernansanz-Agustín, Pablo; Elorza, Ainara; Escasany, Elia; Li, Qilong Oscar Yang; Torres-Capelli, Mar; Tello, Daniel; Fuertes, Esther; Fraga, Enrique; Martínez‐Ruiz, Antonio; Pérez, Belén; Giménez-Bachs, José M.; Salinas-Sánchez, Antonio S.; Acker, Till; Prieto, Ricardo Sánchez; Fendt, Sarah-Maria; Bock, Katrien De; Aragonés, Julián

doi:10.1016/j.celrep.2019.01.106

Cited by 67 publications

(57 citation statements)

References 35 publications

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“…The activation of the HIF pathway in solid tumors is a common phenomenon and has been linked to high proliferation, angiogenesis and poor prognosis in different cancers [16,17,40]. Importantly, we and others have previously demonstrated that the HIF pathway also entails tumor-suppressive components and can reduce tumor proliferation and growth [1,22], possibly explaining the benign properties of KLF4 K409Q mutated tumors. Prototype tumor mutational changes of PI3K, p53 and pVHL in several cancers have been shown to converge on the HIF pathway, directly or indirectly altering HIF's translation, its degradation and the activity of its downstream targets [14].…”

Section: Discussionmentioning

confidence: 78%

KLF4K409Q–mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

Spreckelsen

Waldt

Poetschke

et al. 2020

acta neuropathol commun

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Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4 K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4 K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4 K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4 K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

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Section: Discussionmentioning

confidence: 78%

KLF4K409Q–mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

Spreckelsen

Waldt

Poetschke

et al. 2020

acta neuropathol commun

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“…Further, HIF1A is shown to inhibit the flux from glycolysis to the TCA cycle and promote glutamine reductive carboxylation (reverse TCA flux) for citrate generation. Interestingly, HIF1A is also shown to suppress the expression of aspartate producing genes GOT1 and GOT2 33 . We also found argininosuccinate synthase 1 (ASS1) expression was downregulated, which can increase aspartate availability and is associated with poor prognosis in multiple cancers 34,35 .…”

Section: Discussionmentioning

confidence: 99%

Network-based metabolic characterization of renal cell carcinoma

Pandey

Lanke

Vinod

2020

Sci Rep

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An emerging hallmark of cancer is metabolic reprogramming, which presents opportunities for cancer diagnosis and treatment based on metabolism. We performed a comprehensive metabolic network analysis of major renal cell carcinoma (Rcc) subtypes including clear cell, papillary and chromophobe by integrating transcriptomic data with the human genome-scale metabolic model to understand the coordination of metabolic pathways in cancer cells. We identified metabolic alterations of each subtype with respect to tumor-adjacent normal samples and compared them to understand the differences between subtypes. We found that genes of amino acid metabolism and redox homeostasis are significantly altered in RCC subtypes. Chromophobe showed metabolic divergence compared to other subtypes with upregulation of genes involved in glutamine anaplerosis and aspartate biosynthesis. A difference in transcriptional regulation involving HIF1A is observed between subtypes. We identified E2F1 and FOXM1 as other major transcriptional activators of metabolic genes in RCC. Further, the co-expression pattern of metabolic genes in each patient showed the variations in metabolism within RCC subtypes. We also found that co-expression modules of each subtype have tumor stage-specific behavior, which may have clinical implications. Major biological processes namely reproduction, development, wound healing and tissue regeneration require cell proliferation. Cells proliferate in response to growth-promoting stimulus however, under adverse conditions they move into a reversible, non-proliferating state termed quiescence. Cells gauge the strength of proliferative and anti-proliferative signals through multiple molecular players to make cellular decisions. Cancer is a proliferative disease that arises when the regulatory control of quiescence-proliferation reversible transition is lost. An emerging hallmark of cancer is metabolic reprogramming, which helps to meet the energy demand for cell growth and division. Initial studies by Otto Warburg pointed to aerobic glycolysis, however recent advances have started to reveal other metabolic alterations and plasticity of cancer metabolism 1,2. Understanding the differences in metabolism between normal and cancer cells can shed light on the adaptations that promote disease progression and may also facilitate the identification of therapeutic metabolic targets. Mutations or epigenetic alterations in cancer can influence the expression of metabolic genes. Studies have explored transcriptome data of different cancers to understand the transcriptional dysregulation of metabolic genes. These studies are based on data generated by The Cancer Genome Atlas (TCGA) program. A pan-cancer analysis of different cancer types found a convergent metabolic landscape with upregulated nucleotide synthesis and downregulated mitochondrial metabolism as the main features 3. Rosario et al. 4 analyzed the gene expression of metabolic pathways in Kyoto Encyclopedia of Genes and Genomes (KEGG) and found that pentose and glucuronate inter...

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“…Several recent studies have demonstrated an important role for aspartate in cancer cell proliferation under hypoxia, electron transport chain (ETC)-deficient or inhibited conditions, and in glutamine-limited settings (48–53). Treating HMEC-1 cells with high levels of exogenous aspartate did not affect their growth in hypoxia or normoxia (S4 Fig B).…”

Section: Resultsmentioning

confidence: 99%

“…Decreased aspartate levels have been observed in cancer cells in hypoxia or ETC-deficient or inhibited conditions (48–51,53). Sullivan et al .…”

Section: Discussionmentioning

confidence: 99%

Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia

Cohen

Geck

Toker

2020

Preprint

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21 The vasculature within a tumor is highly disordered both structurally and functionally. Endothelial 22 cells that comprise the vasculature are poorly connected causing vessels to be leaky and exposing 23 the endothelium to a hypoxic microenvironment. Therefore, most anti-angiogenic therapies are 24 generally inefficient and result in acquired resistance to increased hypoxia due to elimination of 25 the vasculature. Recent studies have explored the efficacy of targeting metabolic pathways in 26 tumor cells in combination with anti-angiogenic therapy. However, the metabolic alterations of 27 endothelial cells in response to hypoxia has been relatively unexplored. Here, we measured polar 28 metabolite levels in microvascular endothelial cells exposed to short-and long-term hypoxia with 29 the goal of identifying metabolic vulnerabilities that can be targeted to normalize tumor 30 vasculature and improve drug delivery. Many amino acid-related metabolites were altered by 31 hypoxia exposure, especially within alanine-aspartate-glutamate, serine-threonine, and cysteine-32 methionine metabolism. Additionally, there were significant changes in de novo pyrimidine 33 synthesis as well as glutathione and taurine metabolism. These results provide key insights into 34 the metabolic alterations that occur in endothelial cells in response to hypoxia, which serve as a 35 foundation for future studies to develop therapies that lead to vessel normalization and more 36 efficient drug delivery. Introduction 38The tumor vasculature is highly disordered with both dense regions of vessels and areas 39 that lack vessels. This leads to inefficient blood flow and delivery of nutrients to a tumor, resulting 40 in a microenvironment that is nutrient-poor and hypoxic (1-3). The endothelial cells that comprise 41 disordered vessels are not tightly connected, resulting in leaky vessels (4,5) and exposing 3 42 endothelial cells to a hypoxic environment. This leakiness also enables tumor cell intravasation 43 and metastasis, and significantly impedes efficient drug delivery to tumors (1,3,6-9). Therefore, a 44 number of therapeutic approaches in cancer treatment have focused on normalizing the disordered 45 tumor vasculature. 46Traditionally, the goal of anti-angiogenic therapies (AATs) was to eradicate the vasculature 47 and deprive tumors of nutrients (10). Many AATs are approved or in clinical trials for treatment 48 of solid tumors as monotherapies or in combination with chemotherapy (9,11-15). However, 49 tumors adapt to the hypoxic microenvironment induced by AATs and develop resistance to therapy 50 (16-22). To overcome these limitations, an alternative approach to targeting the tumor vasculature 51 has been explored, whereby pruning and normalization of the tumor vasculature promotes the 52 highly ordered vasculature found within normal tissues. The resulting increased oxygenation and 53 blood flow in turn allows efficient drug delivery (1,3,23). Normalization of the tumor vasculature 54 has been achieved in several clinical studies f...

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HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis

Cited by 67 publications

References 35 publications

KLF4K409Q–mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

KLF4K409Q–mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

Network-based metabolic characterization of renal cell carcinoma

Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia

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