Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells
Abstract DNA repair promotes the progression and recurrence of glioblastoma (GBM). However, there remain no effective therapies for targeting the DNA damage response and repair (DDR) pathway in the clinical setting. Thus, we aimed to conduct a comprehensive analysis of DDR genes in GBM specimens to...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04182-w |
| _version_ | 1818587431465648128 |
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| author | Wen-Bin Yang An-Chih Wu Tsung-I Hsu Jing-Ping Liou Wei-Lun Lo Kwang-Yu Chang Pin-Yuan Chen Ushio Kikkawa Shung-Tai Yang Tzu-Jen Kao Ruei-Ming Chen Wen-Chang Chang Chiung-Yuan Ko Jian-Ying Chuang |
| author_facet | Wen-Bin Yang An-Chih Wu Tsung-I Hsu Jing-Ping Liou Wei-Lun Lo Kwang-Yu Chang Pin-Yuan Chen Ushio Kikkawa Shung-Tai Yang Tzu-Jen Kao Ruei-Ming Chen Wen-Chang Chang Chiung-Yuan Ko Jian-Ying Chuang |
| author_sort | Wen-Bin Yang |
| collection | DOAJ |
| description | Abstract DNA repair promotes the progression and recurrence of glioblastoma (GBM). However, there remain no effective therapies for targeting the DNA damage response and repair (DDR) pathway in the clinical setting. Thus, we aimed to conduct a comprehensive analysis of DDR genes in GBM specimens to understand the molecular mechanisms underlying treatment resistance. Herein, transcriptomic analysis of 177 well-defined DDR genes was performed with normal and GBM specimens (n = 137) from The Cancer Genome Atlas and further integrated with the expression profiling of histone deacetylase 6 (HDAC6) inhibition in temozolomide (TMZ)-resistant GBM cells and patient-derived tumor cells. The effects of HDAC6 inhibition on DDR signaling were examined both in vitro and intracranial mouse models. We found that the expression of DDR genes, involved in repair pathways for DNA double-strand breaks, was upregulated in highly malignant primary and recurrent brain tumors, and their expression was related to abnormal clinical features. However, a potent HDAC6 inhibitor, MPT0B291, attenuated the expression of these genes, including RAD51 and CHEK1, and was more effective in blocking homologous recombination repair in GBM cells. Interestingly, it resulted in lower cytotoxicity in primary glial cells than other HDAC6 inhibitors. MPT0B291 reduced the growth of both TMZ-sensitive and TMZ-resistant tumor cells and prolonged survival in mouse models of GBM. We verified that HDAC6 regulated DDR genes by affecting Sp1 expression, which abolished MPT0B291-induced DNA damage. Our findings uncover a regulatory network among HDAC6, Sp1, and DDR genes for drug resistance and survival of GBM cells. Furthermore, MPT0B291 may serve as a potential lead compound for GBM therapy. |
| first_indexed | 2024-12-16T09:08:45Z |
| format | Article |
| id | doaj.art-0550dd11627c4cb1b510f29cabb3b452 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-16T09:08:45Z |
| publishDate | 2021-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-0550dd11627c4cb1b510f29cabb3b4522022-12-21T22:37:01ZengNature Publishing GroupCell Death and Disease2041-48892021-09-01121011310.1038/s41419-021-04182-wHistone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cellsWen-Bin Yang0An-Chih Wu1Tsung-I Hsu2Jing-Ping Liou3Wei-Lun Lo4Kwang-Yu Chang5Pin-Yuan Chen6Ushio Kikkawa7Shung-Tai Yang8Tzu-Jen Kao9Ruei-Ming Chen10Wen-Chang Chang11Chiung-Yuan Ko12Jian-Ying Chuang13TMU Research Center of Neuroscience, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityTMU Research Center of Neuroscience, Taipei Medical UniversitySchool of Pharmacy, College of Pharmacy, Taipei Medical UniversityDepartment of Neurosurgery, Shuang Ho Hospital, Taipei Medical UniversityNational Institute of Cancer Research, National Health Research InstitutesDepartment of Neurosurgery, Keelung Chang Gung Memorial HospitalGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityDepartment of Neurosurgery, Shuang Ho Hospital, Taipei Medical UniversityTMU Research Center of Neuroscience, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityTMU Research Center of Neuroscience, Taipei Medical UniversityTMU Research Center of Neuroscience, Taipei Medical UniversityAbstract DNA repair promotes the progression and recurrence of glioblastoma (GBM). However, there remain no effective therapies for targeting the DNA damage response and repair (DDR) pathway in the clinical setting. Thus, we aimed to conduct a comprehensive analysis of DDR genes in GBM specimens to understand the molecular mechanisms underlying treatment resistance. Herein, transcriptomic analysis of 177 well-defined DDR genes was performed with normal and GBM specimens (n = 137) from The Cancer Genome Atlas and further integrated with the expression profiling of histone deacetylase 6 (HDAC6) inhibition in temozolomide (TMZ)-resistant GBM cells and patient-derived tumor cells. The effects of HDAC6 inhibition on DDR signaling were examined both in vitro and intracranial mouse models. We found that the expression of DDR genes, involved in repair pathways for DNA double-strand breaks, was upregulated in highly malignant primary and recurrent brain tumors, and their expression was related to abnormal clinical features. However, a potent HDAC6 inhibitor, MPT0B291, attenuated the expression of these genes, including RAD51 and CHEK1, and was more effective in blocking homologous recombination repair in GBM cells. Interestingly, it resulted in lower cytotoxicity in primary glial cells than other HDAC6 inhibitors. MPT0B291 reduced the growth of both TMZ-sensitive and TMZ-resistant tumor cells and prolonged survival in mouse models of GBM. We verified that HDAC6 regulated DDR genes by affecting Sp1 expression, which abolished MPT0B291-induced DNA damage. Our findings uncover a regulatory network among HDAC6, Sp1, and DDR genes for drug resistance and survival of GBM cells. Furthermore, MPT0B291 may serve as a potential lead compound for GBM therapy.https://doi.org/10.1038/s41419-021-04182-w |
| spellingShingle | Wen-Bin Yang An-Chih Wu Tsung-I Hsu Jing-Ping Liou Wei-Lun Lo Kwang-Yu Chang Pin-Yuan Chen Ushio Kikkawa Shung-Tai Yang Tzu-Jen Kao Ruei-Ming Chen Wen-Chang Chang Chiung-Yuan Ko Jian-Ying Chuang Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells Cell Death and Disease |
| title | Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells |
| title_full | Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells |
| title_fullStr | Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells |
| title_full_unstemmed | Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells |
| title_short | Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells |
| title_sort | histone deacetylase 6 acts upstream of dna damage response activation to support the survival of glioblastoma cells |
| url | https://doi.org/10.1038/s41419-021-04182-w |
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