P4HA1 mediates YAP hydroxylation and accelerates collagen synthesis in temozolomide-resistant glioblastoma.
10.1097/CM9.0000000000003679
- Author:
Xueru LI
1
;
Gangfeng YU
2
;
Xiao ZHONG
1
;
Jiacheng ZHONG
2
;
Xiangyu CHEN
1
;
Qinglong CHEN
1
;
Jinjiang XUE
1
;
Xi YANG
1
;
Xinchun ZHANG
1
;
Yao LING
3
;
Yun XIU
1
;
Yaqi DENG
1
;
Hongda LI
1
;
Wei MO
1
;
Yong ZHU
3
;
Ting ZHANG
4
;
Liangjun QIAO
3
;
Song CHEN
2
;
Fanghui LU
1
Author Information
1. 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, China.
2. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
3. School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
4. Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
- Publication Type:Journal Article
- Keywords:
Chemoresistance;
Collagen;
Glioblastoma;
Prolyl 4-hydroxylase subunit alpha 1;
Temozolomide;
Yes-associated protein
- MeSH:
Temozolomide;
Humans;
Glioblastoma/drug therapy*;
Animals;
Mice;
Cell Line, Tumor;
Drug Resistance, Neoplasm/genetics*;
YAP-Signaling Proteins;
Hydroxylation;
Dacarbazine/pharmacology*;
Adaptor Proteins, Signal Transducing/metabolism*;
Transcription Factors/metabolism*;
Collagen/biosynthesis*;
Collagen Type I/metabolism*;
Prolyl Hydroxylases/metabolism*;
Antineoplastic Agents, Alkylating/therapeutic use*
- From:
Chinese Medical Journal
2025;138(16):1991-2005
- CountryChina
- Language:English
-
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.
