Valproic acid targets IDH1 mutants through alteration of lipid metabolism
Abstract Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-seizure medication and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors i...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-08-01
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| Series: | npj Metabolic Health and Disease |
| Online Access: | https://doi.org/10.1038/s44324-024-00021-6 |
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| author | Lubayna S. Elahi Michael C. Condro Riki Kawaguchi Yue Qin Alvaro G. Alvarado Brandon Gruender Haocheng Qi Tie Li Albert Lai Maria G. Castro Pedro R. Lowenstein Matthew C. Garrett Harley I. Kornblum |
| author_facet | Lubayna S. Elahi Michael C. Condro Riki Kawaguchi Yue Qin Alvaro G. Alvarado Brandon Gruender Haocheng Qi Tie Li Albert Lai Maria G. Castro Pedro R. Lowenstein Matthew C. Garrett Harley I. Kornblum |
| author_sort | Lubayna S. Elahi |
| collection | DOAJ |
| description | Abstract Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-seizure medication and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild-type tumors. Surprisingly, genes upregulated by VPA showed no enhanced chromatin accessibility at the promoter, but there was a correlation between VPA-downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decreases in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA inhibited the mTOR pathway and a key lipogenic gene, fatty acid synthase (FASN). Both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find that HDACs are involved in the regulation of lipogenic genes and HDAC6 is particularly important for the regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in an IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic opportunity in IDH1 mutant gliomas. |
| format | Article |
| id | doaj-art-ecf370d8942a4622b169a6b1429e57e4 |
| institution | Kabale University |
| issn | 2948-2828 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Metabolic Health and Disease |
| spelling | doaj-art-ecf370d8942a4622b169a6b1429e57e42025-02-09T12:11:53ZengNature Portfolionpj Metabolic Health and Disease2948-28282024-08-012111410.1038/s44324-024-00021-6Valproic acid targets IDH1 mutants through alteration of lipid metabolismLubayna S. Elahi0Michael C. Condro1Riki Kawaguchi2Yue Qin3Alvaro G. Alvarado4Brandon Gruender5Haocheng Qi6Tie Li7Albert Lai8Maria G. Castro9Pedro R. Lowenstein10Matthew C. Garrett11Harley I. Kornblum12Department of Psychiatry and Behavioral Sciences and the UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLADepartment of Psychiatry and Behavioral Sciences and the UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLADepartment of Neurology, David Geffen School of Medicine, UCLADepartment of Neurology, David Geffen School of Medicine, UCLADepartment of Psychiatry and Behavioral Sciences and the UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLADepartment of Psychiatry and Behavioral Sciences and the UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLADepartment of Psychiatry and Behavioral Sciences and the UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLADepartment of Neurology, David Geffen School of Medicine, UCLADepartment of Neurology, David Geffen School of Medicine, UCLADepartment of Neurosurgery, Department of Cell and Developmental Biology, and Rogel Cancer Center, University of Michigan Medical SchoolDepartment of Neurosurgery, Department of Cell and Developmental Biology, and Rogel Cancer Center, University of Michigan Medical SchoolKettering Health NetworkDepartment of Psychiatry and Behavioral Sciences and the UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLAAbstract Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-seizure medication and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild-type tumors. Surprisingly, genes upregulated by VPA showed no enhanced chromatin accessibility at the promoter, but there was a correlation between VPA-downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decreases in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA inhibited the mTOR pathway and a key lipogenic gene, fatty acid synthase (FASN). Both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find that HDACs are involved in the regulation of lipogenic genes and HDAC6 is particularly important for the regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in an IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic opportunity in IDH1 mutant gliomas.https://doi.org/10.1038/s44324-024-00021-6 |
| spellingShingle | Lubayna S. Elahi Michael C. Condro Riki Kawaguchi Yue Qin Alvaro G. Alvarado Brandon Gruender Haocheng Qi Tie Li Albert Lai Maria G. Castro Pedro R. Lowenstein Matthew C. Garrett Harley I. Kornblum Valproic acid targets IDH1 mutants through alteration of lipid metabolism npj Metabolic Health and Disease |
| title | Valproic acid targets IDH1 mutants through alteration of lipid metabolism |
| title_full | Valproic acid targets IDH1 mutants through alteration of lipid metabolism |
| title_fullStr | Valproic acid targets IDH1 mutants through alteration of lipid metabolism |
| title_full_unstemmed | Valproic acid targets IDH1 mutants through alteration of lipid metabolism |
| title_short | Valproic acid targets IDH1 mutants through alteration of lipid metabolism |
| title_sort | valproic acid targets idh1 mutants through alteration of lipid metabolism |
| url | https://doi.org/10.1038/s44324-024-00021-6 |
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