P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastoma
Abstract. Background:. Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells repro...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer
2025-08-01
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| Series: | Chinese Medical Journal |
| Online Access: | http://journals.lww.com/10.1097/CM9.0000000000003679 |
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| author | Xueru Li Gangfeng Yu Xiao Zhong Jiacheng Zhong Xiangyu Chen Qinglong Chen Jinjiang Xue Xi Yang Xinchun Zhang Yao Ling Yun Xiu Yaqi Deng Hongda Li Wei Mo Yong Zhu Ting Zhang Liangjun Qiao Song Chen Fanghui Lu Xuehong Zhang |
| author_facet | Xueru Li Gangfeng Yu Xiao Zhong Jiacheng Zhong Xiangyu Chen Qinglong Chen Jinjiang Xue Xi Yang Xinchun Zhang Yao Ling Yun Xiu Yaqi Deng Hongda Li Wei Mo Yong Zhu Ting Zhang Liangjun Qiao Song Chen Fanghui Lu Xuehong Zhang |
| author_sort | Xueru Li |
| collection | DOAJ |
| description | Abstract.
Background:. Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens.
Methods:. Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ.
Results:. This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 (COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival.
Conclusion:. P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM. |
| format | Article |
| id | doaj-art-86c1ff39ddfc43f0bac152699eb3d2f8 |
| institution | Kabale University |
| issn | 0366-6999 2542-5641 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wolters Kluwer |
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| series | Chinese Medical Journal |
| spelling | doaj-art-86c1ff39ddfc43f0bac152699eb3d2f82025-08-21T03:04:14ZengWolters KluwerChinese Medical Journal0366-69992542-56412025-08-01138161991200510.1097/CM9.0000000000003679202508200-00010P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastomaXueru Li0Gangfeng Yu1Xiao Zhong2Jiacheng Zhong3Xiangyu Chen4Qinglong Chen5Jinjiang Xue6Xi Yang7Xinchun Zhang8Yao Ling9Yun Xiu10Yaqi Deng11Hongda Li12Wei Mo13Yong Zhu14Ting Zhang15Liangjun Qiao16Song Chen17Fanghui Lu18Xuehong Zhang1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China2 Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China2 Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China3 School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, China3 School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China5 Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China3 School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China2 Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China1 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 404100, ChinaAbstract. Background:. Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. Methods:. Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. Results:. This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 (COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. Conclusion:. P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.http://journals.lww.com/10.1097/CM9.0000000000003679 |
| spellingShingle | Xueru Li Gangfeng Yu Xiao Zhong Jiacheng Zhong Xiangyu Chen Qinglong Chen Jinjiang Xue Xi Yang Xinchun Zhang Yao Ling Yun Xiu Yaqi Deng Hongda Li Wei Mo Yong Zhu Ting Zhang Liangjun Qiao Song Chen Fanghui Lu Xuehong Zhang P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastoma Chinese Medical Journal |
| title | P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastoma |
| title_full | P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastoma |
| title_fullStr | P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastoma |
| title_full_unstemmed | P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastoma |
| title_short | P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastoma |
| title_sort | p4ha1 mediates yap hydroxylation and accelerates collagen synthesis in temozolomide resistant glioblastoma |
| url | http://journals.lww.com/10.1097/CM9.0000000000003679 |
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