2. Academic Validation
  3. PXD101 inhibits malignant progression and radioresistance of glioblastoma by upregulating GADD45A

PXD101 inhibits malignant progression and radioresistance of glioblastoma by upregulating GADD45A

  • J Transl Med. 2024 Nov 20;22(1):1047. doi: 10.1186/s12967-024-05874-5.
Xiaohong Hu # 1 2 3,  Peijun Zhou # 1 2,  Xingzhi Peng 1 2,  Yiting Ouyang 1 2,  Dan Li 3,  Xia Wu 4 5,  Lifang Yang 6 7
Affiliations

Affiliations

  • 1 Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Xiangya Road 110, Changsha, 410078, China.
  • 2 Cancer Research Institute, School of Basic Medicine Science, Central South University, Changsha, 410078, China.
  • 3 Institute of Molecular Medicine and Oncology, College of Biology, Hunan University, Changsha, 410012, China.
  • 4 Cancer Research Institute, School of Basic Medicine Science, Central South University, Changsha, 410078, China. aileenwu@csu.edu.cn.
  • 5 Department of Pathology, The Second Xiangya Hospital, Central South University, Renmin Middle Road 174, Changsha, 410011, China. aileenwu@csu.edu.cn.
  • 6 Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Xiangya Road 110, Changsha, 410078, China. yanglifang@csu.edu.cn.
  • 7 Cancer Research Institute, School of Basic Medicine Science, Central South University, Changsha, 410078, China. yanglifang@csu.edu.cn.
  • # Contributed equally.
PMID: 39568000 DOI: 10.1186/s12967-024-05874-5
Abstract

Histone deacetylase inhibitors (HDACis) have shown a significant antitumor effect in clinical studies, and PXD101 is a novel HDACi which can cross the blood-brain barrier. In this study, we showed that PXD101 could significantly inhibit the proliferation and invasion of glioblastoma (GBM) cells, while promoting their Apoptosis and radiosensitivity. Furthermore, it was found that PXD101 exerted its antitumor function by upregulating the expression of the growth arrest and DNA damage inducible protein α (GADD45A). Mechanistically, PXD101 promoted the transcription of GADD45A by directly acetylating the histones H3 and H4, and GADD45A enhanced Apoptosis and radiosensitivity through the activation of P38 in the GBM cells. In vivo experiments also showed that PXD101 combined with radiotherapy could significantly inhibit the growth of GBM. This study provides experimental evidence for application of the novel HDACi PXD101 in the treatment of GBM, as well as new molecular markers and potential intervention targets that may be used in preventing GBM malignant progression and radioresistance.

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