scholarly journals HBx regulates fatty acid oxidation to promote hepatocellular carcinoma survival during metabolic stress

Oncotarget ◽  
2016 ◽  
Vol 7 (6) ◽  
pp. 6711-6726 ◽  
Author(s):  
Ming-Da Wang ◽  
Han Wu ◽  
Shuai Huang ◽  
Hui-Lu Zhang ◽  
Chen-Jie Qin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Stress ◽  
Acid Oxidation

High PRMT1 Expression Promotes the Progression of Acute Megakaryocytic Leukemia Via Controlling Metabolic Pathways

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1551-1551
Author(s):  
Hairui Su ◽  
Han Guo ◽  
Ngoc-Tung Tran ◽  
Minkui Luo ◽  
Xinyang Zhao
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Pathways ◽  
Metabolic Stress ◽  
Metabolic Reprogramming ◽  
Metabolic Inhibitors ◽  
Acid Oxidation ◽  
Epigenetic Changes ◽  
Acute Megakaryocytic Leukemia ◽  
Megakaryocyte Differentiation

Abstract Metabolic reprogramming is needed not only to accommodate but also to drive leukemia progression. Yet very little is known on genetic factors other than IDH1 mutations, which can drive leukemogenesis via metabolic reprogramming. Here, we will present data to suggest that protein arginine methyltransferases 1 (PRMT1) is a driver for acute megakaryocytic leukemia via reprogramming metabolism. PRMT1 is highly expressed in megakaryocyte-erythrocyte progenitor cells and downregulated during the terminal differentiation of megakaryocytes. Constitutively high expression of PRMT1 in acute megakaryoblastic leukemia (AMKL) blocks megakaryocyte differentiation. PRMT1 upregulates RBM15 protein level via methylation-dependent ubiquitylation pathway (Zheng et al. Elife, 2015). In this presentation, we discovered that metabolic stress such as hypoxia downregulates PRMT1 protein level. Thus, metabolic stress is the upstream signal for the PRMT1-RBM15 pathway. We have identified that RBM15 specifically binds to 3'UTR of mRNAs of genes involved in metabolic pathways. Using RNA-immunoprecipitation with anti-RBM15 antibody and real-time PCR assays, we validated that RBM15 binds to mRNAs of genes involved in fatty acid oxidation and glycolysis. We transduced PRMT1 into an RBM15-MKL1 expressing cell line 6133. Overexpression of PRMT1 renders 6133 cells to grow in a cytokine-independent manner with increased mitochondria biogenesis, which in turn produces higher concentration of ATP in our metabolomic analysis. Based on the analysis of metabolomics data and RBM15-target genes, we conclude that PRMT1 promotes the usage of glucose as bioenergy via oxidative phosphorylation and inhibits fatty acid oxidation. Given that acetyl-coA is higher in PRMT1 expressing 6133 cells, we asked whether histone acetylation is upregulated in PRMT1 overexpressed 6133 cells. Indeed, we found higher histone acetylation level in PRMT1 highly expressed cells. We also found that propionylated histone is reduced, which is consistent with reduced fatty acid oxidation. Propionyl-CoA molecules are produced from fatty acids with odd carbon numbers. Thus PRMT1-mediated metabolic reprogramming changes epigenetic programming during leukemia progression. Intriguing, we also found PRMT1 overexpression enhances histone H3S10 phosphorylation via methylation-dependent ubiquitylation of DUSP4. DUSP4 promotes polyploidy during megakaryocyte differentiation. Thus PRMT1 caused profound epigenetic changes to promote leukemogenesis. In this vein, we established mouse AMKL models by bone marrow transplantation of 6133 cells as well as human AMKL patient samples respectively. Using this mouse model, we tested PRMT1 inhibitors, acetyltransferase inhibitors as well as other metabolic inhibitors. Treating cells with PRMT1 inhibitors as well as metabolic inhibitors promote MK differentiation of AMKL leukemia cells. Metabolomics analysis of cells recovered from mouse models will be discussed in the presentation. In summary, our data demonstrated that PRMT1 is a major sensor for metabolic stress and that PRMT1 in turn reprograms metabolic pathways to bring epigenetic changes in leukemogenesis. Therefore, targeting PRMT1 and downstream PRMT1-regulated metabolic pathways will offer new avenues in treating acute megakaryocytic leukemia and other hematological malignancies with defective megakaryocyte differentiation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation

2018 ◽  
Vol 69 (3) ◽  
pp. 480-492.e7 ◽  
Author(s):  
Xiao-xue Li ◽  
Zhi-jing Wang ◽  
Yu Zheng ◽  
Yun-feng Guan ◽  
Peng-bo Yang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cell Survival ◽  
Fatty Acid Oxidation ◽  
Nuclear Receptor ◽  
Melanoma Cell ◽  
Metabolic Stress ◽  
Acid Oxidation

scholarly journals SG-04 * THE eEF2 KINASE, A MEDIATOR OF MEDULLOBLASTOMA ADAPTATION TO METABOLIC STRESS, SUPPORTS FATTY ACID OXIDATION

2015 ◽  
Vol 17 (suppl 3) ◽  
pp. iii35-iii35
Author(s):  
G. Leprivier ◽  
R. Teperino ◽  
A. Kristensen ◽  
M. Remke ◽  
S. Pfister ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Stress ◽  
Acid Oxidation ◽  
Eef2 Kinase ◽  
Kinase A

scholarly journals Hearts lacking plasma membrane KATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity

2017 ◽  
Vol 313 (3) ◽  
pp. H469-H478 ◽  
Author(s):  
Nermeen Youssef ◽  
Scott Campbell ◽  
Amy Barr ◽  
Manoj Gandhi ◽  
Beth Hunter ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Metabolic Stress ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Metabolic Substrate ◽  
Amp Activated Protein Kinase

Cardiac ATP-sensitive K+ (KATP) channels couple changes in cellular metabolism to membrane excitability and are activated during metabolic stress, although under basal aerobic conditions, KATP channels are thought to be predominately closed. Despite intense research into the roles of KATP channels during metabolic stress, their contribution to aerobic basal cardiac metabolism has not been previously investigated. Hearts from Kir6.2+/+ and Kir6.2−/− mice were perfused in working mode, and rates of glycolysis, fatty acid oxidation, and glucose oxidation were measured. Changes in activation/expression of proteins regulating metabolism were probed by Western blot analysis. Despite cardiac mechanical function and metabolic efficiency being similar in both groups, hearts from Kir6.2−/− mice displayed an approximately twofold increase in fatty acid oxidation and a 0.45-fold reduction in glycolytic rates but similar glucose oxidation rates compared with hearts from Kir6.2+/+ mice. Kir6.2−/− hearts also possessed elevated levels of activated AMP-activated protein kinase (AMPK), higher glycogen content, and reduced mitochondrial density. Moreover, activation of AMPK by isoproterenol or diazoxide was significantly blunted in Kir6.2−/− hearts. These data indicate that KATP channel ablation alters aerobic basal cardiac metabolism. The observed increase in fatty acid oxidation and decreased glycolysis before any metabolic insult may contribute to the poor recovery observed in Kir6.2−/− hearts in response to exercise or ischemia-reperfusion injury. Therefore, KATP channels may play an important role in the regulation of cardiac metabolism through AMPK signaling. NEW & NOTEWORTHY In this study, we show that genetic ablation of plasma membrane ATP-sensitive K+ channels results in pronounced changes in cardiac metabolic substrate preference and AMP-activated protein kinase activity. These results suggest that ATP-sensitive K+ channels may play a novel role in regulating metabolism in addition to their well-documented effects on ionic homeostasis during periods of stress.

Suppression of ACADM-mediated fatty acid oxidation promotes hepatocellular carcinoma via aberrant Cav1/SREBP-1 signaling

2021 ◽  
pp. canres.3944.2020
Author(s):  
Angel P. Y. Ma ◽  
Cherlie L. S. Yeung ◽  
Sze Keong Tey ◽  
Xiaowen Mao ◽  
Samuel W. K. Wong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation
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