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P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastoma
Xueru Li1, Gangfeng Yu2,3, Xiao Zhong1
1Department 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, China.
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.
Insights
Glioblastoma cells resist temozolomide by increasing collagen type I via the P4HA1-YAP pathway. Targeting this axis enhances chemoresistance and improves survival in glioblastoma models.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Mechanisms
Background:
- Temozolomide (TMZ) resistance is a major hurdle in glioblastoma (GBM) treatment.
- Collagen remodeling is implicated in therapy resistance across various cancers.
- Understanding GBM's collagen reprogramming mechanisms is crucial for overcoming chemoresistance.
Purpose of the Study:
- To investigate how GBM cells reprogram collagens to develop TMZ chemoresistance.
- To elucidate the molecular pathways involved in collagen accumulation in GBM.
- To assess the therapeutic potential of targeting collagen regulators in GBM.
Main Methods:
- Analysis of collagen in patient samples and GBM murine models.
- In vitro studies using human and mouse GBM cell lines.
- RNA-sequencing, ChIP, IP-MS, and co-IP assays to identify molecular mechanisms.
- In vitro and in vivo experiments to evaluate P4HA1 and YAP roles in TMZ sensitivity.
Main Results:
- TMZ exposure increased collagen type I (COL I) expression in GBM.
- Collagen accumulation enhanced GBM cell survival and TMZ resistance.
- P4HA1 stabilized YAP by preventing its degradation, promoting COL1A1 transcription and collagen deposition.
- Disrupting the P4HA1-YAP axis reduced COL I, sensitized cells to TMZ, and improved survival in mice.
Conclusions:
- P4HA1 drives YAP-mediated COL1A1 transcription, leading to collagen accumulation.
- This collagen accumulation promotes chemoresistance in glioblastoma.
- Targeting the P4HA1-YAP axis offers a potential strategy to overcome TMZ resistance in GBM.
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