exposure significantly elevated collagen type I () expression in both GBM patients and murine models.
Collagen accumulation sustained GBM cell survival under TMZ-induced stress.
P4HA1 directly binds to and modifies , preventing its degradation.
Stabilized YAP enhances the transcription of collagen type I alpha 1 (COL1A1), resulting in increased collagen production.
Disrupting the P4HA1-YAP interaction reduced COL I deposition and sensitized GBM cells to TMZ.
This disruption also led to significantly improved survival in mouse models.
Simplified
BACKGROUND: (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 () in sensitizing GBM cells to TMZ.
RESULTS: This study revealed that TMZ exposure significantly elevated collagen type 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.
Key numbers
17×
Increase in expression
levels in recurrent GBM tissues vs. paired primary samples.
50%
Reduction in deposition
Decrease in levels upon P4HA1 inhibition in GBM cells.
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