HOTAIR‐EZH2 inhibitor AC1Q3QWB upregulates CWF19L1 and enhances cell cycle inhibition of CDK4/6 inhibitor palbociclib in glioma

Clinical and Translational Medicine

Kuanxun Li¹  Yan Deng²  Yansheng Li³  Xingen Zhu⁴  Miaojing Wu⁴  Jin Shi⁴  Minhua Ye⁴  Xianggan Wang⁴  Shigang Lv⁴  Hongyu Zhao⁵ 

[1] Department of Medicine Medical College of Nanchang University Jiangxi P.R. China;Department of Neurology The Second Affiliated Hospital of Nanchang University Jiangxi P.R. China;Department of Neurosurgery Laboratory of Neuro‐Oncology Key Laboratory of Post‐trauma Neuro‐repair and Regeneration in Central Nervous System Ministry of Education Tianjin Key Laboratory of Injuries Tianjin Medical University General Hospital Tianjin Neurological Institute Variations and Regeneration of Nervous System Tianjin P.R. China;Department of Neurosurgery The Second Affiliated Hospital of Nanchang University Jiangxi P.R. China;Department of Neurosurgery Tongji Hospital Huazhong University of Science and Technology Wuhan P.R. China;

关键词: β‐catenin;    AQB;    CDK4;    CDK6;    cell cycle, CWF19L1;    palbociclib;   

DOI  :  10.1002/ctm2.21

来源: DOAJ

【 摘 要 】

Abstract Background Glioblastoma (GBM) is the most common primary tumor in the brain, and the median survival time for GBM patients is only about 14 months; therefore, there is an urgent need for new and more effective strategies. Since cell cycle disorder is a key factor in tumor progression and immortalization, there is great potential for controlling cell cycle disorders in tumor cells in GBM patients. We began to study a novel combination of AQB and palbociclib to evaluate its potential as a new therapeutic target. Methods Protein mass spectrometry was used to identify the tumor suppressor genes up‐regulated by AQB.The effects of HOTAIR ‐ EZH2 inhibitor AQB and CDK4/6 inhibitor Palbociclib on glioma cells lines were examined in vitro and in vivo experiments. Results The combination of AQB and palbociclib inhibitors has a more pronounced suppression effect on the cell cycle, especially gliomas with high expression of HOTAIR and EZH2 and low expression of CWF19L1. We performed protein mass spectrometry to identify AQB upregulated tumor suppressor genes and confirmed that CWF19L1 is regulated by H3K27ac through chromatin immunoprecipitation‐quantitative PCR results. Univariate and multivariate Cox regression analysis and database analysis were performed to suggest CWF19L1 is a good prognostic factor. Our experimental results suggested that CWF19L1 can be significantly upregulated by AQB and lead to degradation of CDK4/6, resulting in G1 arrest. The combination of AQB and CDK4/6 inhibitor palbociclib is more effective in inhibiting the growth of glioma than in the single drug, both in vivo and in vitro. Similarly, we found that both AQB and palbociclib can inhibit Wnt/β‐catenin signaling, and the combined use of the two inhibitors has a stronger inhibitory effect on tumor metastasis. Conclusions The combination of AQB and CDK4/6 inhibitor palbociclib has been found to have significant antitumor effects, which is likely to become a new strategy for glioma treatment.

【 授权许可】

Unknown