Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases
Glioblastoma (GBM) remains an incurable disease with an extremely high five-year recurrence rate. We studied apoptosis in glioma stem cells (GSCs) in response to HDAC inhibition (HDACi) combined with MEK1/2 inhibition (MEKi) or BCL-2 family inhibitors. MEKi effectively combined with HDACi to suppres...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/18/13688 |
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| author | Aran Merati Spandana Kotian Alexus Acton William Placzek Erin Smithberger Abigail K. Shelton C. Ryan Miller Josh L. Stern |
| author_facet | Aran Merati Spandana Kotian Alexus Acton William Placzek Erin Smithberger Abigail K. Shelton C. Ryan Miller Josh L. Stern |
| author_sort | Aran Merati |
| collection | DOAJ |
| description | Glioblastoma (GBM) remains an incurable disease with an extremely high five-year recurrence rate. We studied apoptosis in glioma stem cells (GSCs) in response to HDAC inhibition (HDACi) combined with MEK1/2 inhibition (MEKi) or BCL-2 family inhibitors. MEKi effectively combined with HDACi to suppress growth, induce cell cycle defects, and apoptosis, as well as to rescue the expression of the pro-apoptotic BH3-only proteins BIM and BMF. A RNAseq analysis of GSCs revealed that HDACi repressed the pro-survival BCL-2 family genes MCL1 and BCL-XL. We therefore replaced MEKi with BCL-2 family inhibitors and observed enhanced apoptosis. Conversely, a ligand for the cancer stem cell receptor CD44 led to reductions in BMF, BIM, and apoptosis. Our data strongly support further testing of HDACi in combination with MEKi or BCL-2 family inhibitors in glioma. |
| first_indexed | 2024-03-10T22:40:51Z |
| format | Article |
| id | doaj.art-05ba987375ae444995b4beb91d5aa079 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T22:40:51Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-05ba987375ae444995b4beb91d5aa0792023-11-19T11:01:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124181368810.3390/ijms241813688Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone DeacetylasesAran Merati0Spandana Kotian1Alexus Acton2William Placzek3Erin Smithberger4Abigail K. Shelton5C. Ryan Miller6Josh L. Stern7Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USAO’Neal Comprehensive Cancer Center, Birmingham, AL 35294, USAO’Neal Comprehensive Cancer Center, Birmingham, AL 35294, USAO’Neal Comprehensive Cancer Center, Birmingham, AL 35294, USADepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USAGlioblastoma (GBM) remains an incurable disease with an extremely high five-year recurrence rate. We studied apoptosis in glioma stem cells (GSCs) in response to HDAC inhibition (HDACi) combined with MEK1/2 inhibition (MEKi) or BCL-2 family inhibitors. MEKi effectively combined with HDACi to suppress growth, induce cell cycle defects, and apoptosis, as well as to rescue the expression of the pro-apoptotic BH3-only proteins BIM and BMF. A RNAseq analysis of GSCs revealed that HDACi repressed the pro-survival BCL-2 family genes MCL1 and BCL-XL. We therefore replaced MEKi with BCL-2 family inhibitors and observed enhanced apoptosis. Conversely, a ligand for the cancer stem cell receptor CD44 led to reductions in BMF, BIM, and apoptosis. Our data strongly support further testing of HDACi in combination with MEKi or BCL-2 family inhibitors in glioma.https://www.mdpi.com/1422-0067/24/18/13688glioblastomaapoptosisHDAC inhibitorBIMBMFBCL-2 family |
| spellingShingle | Aran Merati Spandana Kotian Alexus Acton William Placzek Erin Smithberger Abigail K. Shelton C. Ryan Miller Josh L. Stern Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases International Journal of Molecular Sciences glioblastoma apoptosis HDAC inhibitor BIM BMF BCL-2 family |
| title | Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases |
| title_full | Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases |
| title_fullStr | Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases |
| title_full_unstemmed | Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases |
| title_short | Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases |
| title_sort | glioma stem cells are sensitized to bcl 2 family inhibition by compromising histone deacetylases |
| topic | glioblastoma apoptosis HDAC inhibitor BIM BMF BCL-2 family |
| url | https://www.mdpi.com/1422-0067/24/18/13688 |
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