Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL
| Autor: | Kavita Bhalla, Nanaji Nahid M., Ari Landon, Andrew M. Evens, Paul Bastian, Karen Underwood, John D. Haley, Sausan M. Jaber, Binny Bhandary, Brian M. Polster, Afshin Beheshti, Ronald B. Gartenhaus |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
lcsh:Medicine Kinesins Article 03 medical and health sciences immune system diseases hemic and lymphatic diseases medicine Protein biosynthesis Tumor Cells Cultured Animals Humans lcsh:Science Hypoxia Author Correction Regulation of gene expression Gene knockdown Multidisciplinary biology lcsh:R Hypoxia (medical) medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Phenotype Lymphoma 030104 developmental biology Gene Expression Regulation Protein Biosynthesis biology.protein Cancer research GLUT1 lcsh:Q Lymphoma Large B-Cell Diffuse medicine.symptom Diffuse large B-cell lymphoma |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-15 (2018) |
| ISSN: | 2045-2322 |
| Popis: | Published molecular profiling studies in patients with lymphoma suggested the influence of hypoxia inducible factor-1 alpha (HIF1α) targets in prognosis of DLBCL. Yet, the role of hypoxia in hematological malignancies remains unclear. We observed that activation of HIF1α resulted in global translation repression during hypoxic stress in DLBCL. Protein translation efficiency as measured using 35S-labeled methionine incorporation revealed a ≥50% reduction in translation upon activation of HIF1α. Importantly, translation was not completely inhibited and expression of clinically correlated hypoxia targets such as GLUT1, HK2, and CYT-C was found to be refractory to translational repression under hypoxia in DLBCL cells. Notably, hypoxic induction of these genes was not observed in normal primary B-cells. Translational repression was coupled with a decrease in mitochondrial function. Screening of primary DLBCL patient samples revealed that expression of HK2, which encodes for the enzyme hexokinase 2, was significantly correlated with DLBCL phenotype. Genetic knockdown studies demonstrated that HK2 is required for promoting growth of DLBCL under hypoxic stress. Altogether, our findings provide strong support for the direct contribution of HK2 in B-cell lymphoma development and suggest that HK2 is a key metabolic driver of the DLBCL phenotype. |
| Databáze: | OpenAIRE |
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