HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma
Abstract Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-ca...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-33889-3 |
| _version_ | 1797752796505702400 |
|---|---|
| author | Matthew C. Garrett Rebecca Albano Troy Carnwath Lubayna Elahi Catherine A. Behrmann Merissa Pemberton Daniel Woo Eric O’Brien Brett VanCauwenbergh John Perentesis Sanjit Shah Matthew Hagan Ady Kendler Chuntao Zhao Aditi Paranjpe Krishna Roskin Harley Kornblum David R. Plas Q. Richard Lu |
| author_facet | Matthew C. Garrett Rebecca Albano Troy Carnwath Lubayna Elahi Catherine A. Behrmann Merissa Pemberton Daniel Woo Eric O’Brien Brett VanCauwenbergh John Perentesis Sanjit Shah Matthew Hagan Ady Kendler Chuntao Zhao Aditi Paranjpe Krishna Roskin Harley Kornblum David R. Plas Q. Richard Lu |
| author_sort | Matthew C. Garrett |
| collection | DOAJ |
| description | Abstract Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas. |
| first_indexed | 2024-03-12T17:09:39Z |
| format | Article |
| id | doaj.art-cd41171c4c2c402c887577588bb94c39 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-12T17:09:39Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-cd41171c4c2c402c887577588bb94c392023-08-06T11:11:16ZengNature PortfolioScientific Reports2045-23222023-08-0113111210.1038/s41598-023-33889-3HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant gliomaMatthew C. Garrett0Rebecca Albano1Troy Carnwath2Lubayna Elahi3Catherine A. Behrmann4Merissa Pemberton5Daniel Woo6Eric O’Brien7Brett VanCauwenbergh8John Perentesis9Sanjit Shah10Matthew Hagan11Ady Kendler12Chuntao Zhao13Aditi Paranjpe14Krishna Roskin15Harley Kornblum16David R. Plas17Q. Richard Lu18Department of Neurosurgery, University of Cincinnati College of MedicineDepartment of Neurosurgery, University of Cincinnati College of MedicineUniversity of Cincinnati College of MedicineDepartment of Molecular Cell and Developmental Biology, University of California Los AngelesDepartment of Cancer Biology, University of CincinnatiUniversity of Cincinnati College of MedicineDepartment of Neurology, University of Cincinnati College of MedicineDivision of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of MedicineDivision of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of MedicineDivision of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of MedicineDepartment of Neurosurgery, University of Cincinnati College of MedicineDepartment of Pathology and Laboratory Medicine, University of Cincinnati College of MedicineDepartment of Pathology and Laboratory Medicine, University of Cincinnati College of MedicineDivision of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of MedicineBioinformatics Collaborative Services, Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical CenterBioinformatics Collaborative Services, Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical CenterDepartment of Molecular Cell and Developmental Biology, University of California Los AngelesDepartment of Cancer Biology, University of CincinnatiDivision of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of MedicineAbstract Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.https://doi.org/10.1038/s41598-023-33889-3 |
| spellingShingle | Matthew C. Garrett Rebecca Albano Troy Carnwath Lubayna Elahi Catherine A. Behrmann Merissa Pemberton Daniel Woo Eric O’Brien Brett VanCauwenbergh John Perentesis Sanjit Shah Matthew Hagan Ady Kendler Chuntao Zhao Aditi Paranjpe Krishna Roskin Harley Kornblum David R. Plas Q. Richard Lu HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma Scientific Reports |
| title | HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma |
| title_full | HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma |
| title_fullStr | HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma |
| title_full_unstemmed | HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma |
| title_short | HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma |
| title_sort | hdac1 and hdac6 are essential for driving growth in idh1 mutant glioma |
| url | https://doi.org/10.1038/s41598-023-33889-3 |
| work_keys_str_mv | AT matthewcgarrett hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT rebeccaalbano hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT troycarnwath hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT lubaynaelahi hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT catherineabehrmann hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT merissapemberton hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT danielwoo hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT ericobrien hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT brettvancauwenbergh hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT johnperentesis hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT sanjitshah hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT matthewhagan hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT adykendler hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT chuntaozhao hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT aditiparanjpe hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT krishnaroskin hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT harleykornblum hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT davidrplas hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma AT qrichardlu hdac1andhdac6areessentialfordrivinggrowthinidh1mutantglioma |