1. Academic Validation
  2. MZ1, a BRD4 inhibitor, exerted its anti-cancer effects by suppressing SDC1 in glioblastoma

MZ1, a BRD4 inhibitor, exerted its anti-cancer effects by suppressing SDC1 in glioblastoma

  • BMC Cancer. 2024 Feb 16;24(1):220. doi: 10.1186/s12885-024-11966-8.
Gen Li # 1 Liya Ma # 2 Chenxi Feng # 1 Hongli Yin # 1 Jianping Bao # 3 Di Wu 1 Zimu Zhang 1 Xiaolu Li 1 Zhiheng Li 1 Chun Yang 1 Hairong Wang 1 Fang Fang 1 Xiaohan Hu 1 Mei Li 1 Lixiao Xu 1 Yunyun Xu 1 Hansi Liang 4 Tianquan Yang 5 Jianwei Wang 6 Jian Pan 7
Affiliations

Affiliations

  • 1 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215025, P.R. China.
  • 2 College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, 471023, P.R. China.
  • 3 Department of Neonatology, Children's Hospital of Soochow University, Suzhou, 215025, P.R. China.
  • 4 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, P.R. China.
  • 5 Department of Neurosurgery, Children's Hospital of Soochow University, Suzhou, 215025, P.R. China. szdxytq@suda.edu.cn.
  • 6 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215025, P.R. China. lch1239wang@126.com.
  • 7 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215025, P.R. China. panjian2008@163.com.
  • # Contributed equally.
Abstract

Background: Glioblastoma (GBM) is a relatively prevalent primary tumor of the central nervous system in children, characterized by its high malignancy and mortality rates, along with the intricate challenges of achieving complete surgical resection. Recently, an increasing number of studies have focused on the crucial role of super-enhancers (SEs) in the occurrence and development of GBM. This study embarks on the task of evaluating the effectiveness of MZ1, an inhibitor of BRD4 meticulously designed to specifically target SEs, within the intricate framework of GBM.

Methods: The clinical data of GBM patients was sourced from the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the gene expression data of tumor cell lines was derived from the Cancer Cell Line Encyclopedia (CCLE). The impact of MZ1 on GBM was assessed through CCK-8, colony formation assays, EdU incorporation analysis, flow cytometry, and xenograft mouse models. The underlying mechanism was investigated through RNA-seq and ChIP-seq analyses.

Results: In this investigation, we made a noteworthy observation that MZ1 exhibited a substantial reduction in the proliferation of GBM cells by effectively degrading BRD4. Additionally, MZ1 displayed a notable capability in inducing significant cell cycle arrest and Apoptosis in GBM cells. These findings were in line with our in vitro outcomes. Notably, MZ1 administration resulted in a remarkable decrease in tumor size within the xenograft model with diminished toxicity. Furthermore, on a mechanistic level, the administration of MZ1 resulted in a significant suppression of pivotal genes closely associated with cell cycle regulation and epithelial-mesenchymal transition (EMT). Interestingly, our analysis of RNA-seq and ChIP-seq data unveiled the discovery of a novel prospective oncogene, SDC1, which assumed a pivotal role in the tumorigenesis and progression of GBM.

Conclusion: In summary, our findings revealed that MZ1 effectively disrupted the aberrant transcriptional regulation of oncogenes in GBM by degradation of BRD4. This positions MZ1 as a promising candidate in the realm of therapeutic options for GBM treatment.

Keywords

BRD4; GBM; PROTAC; SDC1; SEs.

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