USP7 promotes temozolomide resistance by stabilizing MGMT in glioblastoma
Abstract Glioblastoma (GBM), a World Health Organization (WHO) grade IV glioma, is one of the most lethal brain tumors, with a poor prognosis and limited treatment options. Temozolomide (TMZ), a first-line chemotherapeutic agent, often proves ineffective due to resistance and toxicity associated wit...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07969-3 |
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| _version_ | 1849225843190005760 |
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| author | Jiabing Li Xiaorong Feng Zhaohui Liu Yunfang Deng Zhiming Sun Bei Chen Lihui Wu Xiaolong Wang Lin Miao Liyuan Zeng Lei Hu Yuming He Ying Sheng Yue Liu Yu Zhao |
| author_facet | Jiabing Li Xiaorong Feng Zhaohui Liu Yunfang Deng Zhiming Sun Bei Chen Lihui Wu Xiaolong Wang Lin Miao Liyuan Zeng Lei Hu Yuming He Ying Sheng Yue Liu Yu Zhao |
| author_sort | Jiabing Li |
| collection | DOAJ |
| description | Abstract Glioblastoma (GBM), a World Health Organization (WHO) grade IV glioma, is one of the most lethal brain tumors, with a poor prognosis and limited treatment options. Temozolomide (TMZ), a first-line chemotherapeutic agent, often proves ineffective due to resistance and toxicity associated with overexpressed O 6-methylguanine-DNA-methyltransferase (MGMT). In this study, we identified ubiquitin-specific protease 7 (USP7) as a nuclear regulator of MGMT stability and TMZ resistance. USP7 binds directly to MGMT via its UBL domain, counteracts K48-linked ubiquitin chains, and prevents MGMT proteasomal degradation. This functional relationship is further supported by their nuclear colocalization. Strikingly, this study, together with previous findings, establishes USP7 as a key integrator of all three major alkylation repair pathways through its role in stabilizing alkylation repair proteins. USP7 stabilizes MGMT through a dual mechanism, thereby modulating the direct reversal repair pathway. Inhibition or knockdown of USP7 reduces MGMT levels, as well as those of XPC, ALKBH2, and ALKBH3, impairs DNA repair capacity, and sensitizes GBM cells to TMZ, enabling effective treatment with reduced TMZ dosages. Clinically, tissue microarray analyses reveal that USP7 and MGMT co-overexpression in GBM correlates with poor patient survival. Collectively, our results uncover a new and direct role for USP7 in MGMT-mediated direct reversal repair and TMZ resistance, positioning USP7 as a distinctive integrator of alkylation repair pathways. Targeting USP7 provides mechanistic insights into regulating diverse alkylation repair pathways and offers a strategy to enhance the efficacy of combination chemotherapies, including TMZ and other alkylating agents, by modulating distinct repair mechanisms in GBM. |
| format | Article |
| id | doaj-art-70c57aec904f45dab9e91cf037d4eab9 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-70c57aec904f45dab9e91cf037d4eab92025-08-24T11:54:21ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111310.1038/s41419-025-07969-3USP7 promotes temozolomide resistance by stabilizing MGMT in glioblastomaJiabing Li0Xiaorong Feng1Zhaohui Liu2Yunfang Deng3Zhiming Sun4Bei Chen5Lihui Wu6Xiaolong Wang7Lin Miao8Liyuan Zeng9Lei Hu10Yuming He11Ying Sheng12Yue Liu13Yu Zhao14The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal UniversityAbstract Glioblastoma (GBM), a World Health Organization (WHO) grade IV glioma, is one of the most lethal brain tumors, with a poor prognosis and limited treatment options. Temozolomide (TMZ), a first-line chemotherapeutic agent, often proves ineffective due to resistance and toxicity associated with overexpressed O 6-methylguanine-DNA-methyltransferase (MGMT). In this study, we identified ubiquitin-specific protease 7 (USP7) as a nuclear regulator of MGMT stability and TMZ resistance. USP7 binds directly to MGMT via its UBL domain, counteracts K48-linked ubiquitin chains, and prevents MGMT proteasomal degradation. This functional relationship is further supported by their nuclear colocalization. Strikingly, this study, together with previous findings, establishes USP7 as a key integrator of all three major alkylation repair pathways through its role in stabilizing alkylation repair proteins. USP7 stabilizes MGMT through a dual mechanism, thereby modulating the direct reversal repair pathway. Inhibition or knockdown of USP7 reduces MGMT levels, as well as those of XPC, ALKBH2, and ALKBH3, impairs DNA repair capacity, and sensitizes GBM cells to TMZ, enabling effective treatment with reduced TMZ dosages. Clinically, tissue microarray analyses reveal that USP7 and MGMT co-overexpression in GBM correlates with poor patient survival. Collectively, our results uncover a new and direct role for USP7 in MGMT-mediated direct reversal repair and TMZ resistance, positioning USP7 as a distinctive integrator of alkylation repair pathways. Targeting USP7 provides mechanistic insights into regulating diverse alkylation repair pathways and offers a strategy to enhance the efficacy of combination chemotherapies, including TMZ and other alkylating agents, by modulating distinct repair mechanisms in GBM.https://doi.org/10.1038/s41419-025-07969-3 |
| spellingShingle | Jiabing Li Xiaorong Feng Zhaohui Liu Yunfang Deng Zhiming Sun Bei Chen Lihui Wu Xiaolong Wang Lin Miao Liyuan Zeng Lei Hu Yuming He Ying Sheng Yue Liu Yu Zhao USP7 promotes temozolomide resistance by stabilizing MGMT in glioblastoma Cell Death and Disease |
| title | USP7 promotes temozolomide resistance by stabilizing MGMT in glioblastoma |
| title_full | USP7 promotes temozolomide resistance by stabilizing MGMT in glioblastoma |
| title_fullStr | USP7 promotes temozolomide resistance by stabilizing MGMT in glioblastoma |
| title_full_unstemmed | USP7 promotes temozolomide resistance by stabilizing MGMT in glioblastoma |
| title_short | USP7 promotes temozolomide resistance by stabilizing MGMT in glioblastoma |
| title_sort | usp7 promotes temozolomide resistance by stabilizing mgmt in glioblastoma |
| url | https://doi.org/10.1038/s41419-025-07969-3 |
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