Histone acetyltransferase inhibitor II induces apoptosis in glioma cell lines via the p53 signaling pathway

Journal of Experimental & Clinical Cancer Research

Jian Pan¹  Xing Feng³  Jian Wang²  Yan-Hong Li²  Gang Li²  He Zhao²  Fang Fang²  Rong-Hu Li³  Yan-Fang Tao¹  Zhi-Heng Li²  Li-Xiao Xu² 

[1] Department of Hematology and Oncology, Children’s Hospital of Soochow University, Suzhou 215006, China;Institute of Pediatric Research, Children’s Hospital affiliated to Soochow University, Suzhou 215006, China;Department of Neonatology, Children’s Hospital of Soochow University, Suzhou 215006, China

关键词: p53 signaling pathway;    LncRNA/mRNA;    Apoptosis;    Glioma;    HATi II;   

Others  :  1145423
DOI  :  10.1186/s13046-014-0108-3

 received in 2014-08-08, accepted in 2014-12-01,  发布年份 2014

【 摘 要 】

Background

Histone acetyltransferase (HAT) inhibitors can inhibit proliferation and induce apoptosis in cancer cell lines. The novel cell-permeable p300/CREB-binding protein (CBP)-selective HAT inhibitor HATi II can reduce histone H3 acetylation and induce chromatin condensation in HeLa cells. Here, we examined the effects and mechanism of action of HATi II in glioma cell lines.

Methods

Cell viability was assessed using the CCK-8 assay. Cell cycle analysis was performed using flow cytometry. Apoptosis was evaluated using Annexin V staining and flow cytometry, Hoechst 33342 staining and the TUNEL assay. Expression and cleavage of caspase-3, caspase-9 and poly ADP-ribose polymerase (PARP) were assessed by Western blotting. Statistical analysis was performed using two-tailed Student’s t-tests. The gene expression profiles of U251 glioma cells treated with HATi II or DMSO were analyzed using the Arraystar Human 8 x 60 K LncRNA/mRNA expression array; data was analyzed using MEV (Multi Experiment View) cluster software. Datasets representing genes with altered expression profiles (≥2-fold) derived from the cluster analyses were subjected to gene ontology and pathway analysis.

Results

HATi II inhibited the proliferation of U251, U87, HS683 and SHG44 cells in a dose-dependent manner. HATi II induced cell cycle arrest at the G2/M phase, and induced significant levels of apoptosis, apoptotic body formation and DNA fragmentation in HATi II-treated U251 and SHG44 cells. HATi II induced cleavage of caspase-3, caspase-9 and PARP in U251 and SHG44 cells. In HATi II-treated U251 cells, 965 genes were upregulated, 984 genes were downregulated and 3492/33327 lncRNAs were differentially expressed. GO analysis showed the differentially expressed genes with known functions are involved in a variety of processes; alcoholism, p53 signaling pathway, cytokine-cytokine receptor interaction and transcriptional mis-regulation in cancer were the four most significant pathways. Upregulation of p53 signaling pathway-related genes in HATi II-treated cells was confirmed by quantitative RT-PCR and Western blotting.

Conclusions

HATi II inhibits proliferation and induces apoptosis via the caspase-dependent pathway in human glioma cell lines, possibly by activating the p53 signaling pathway. HATi II deserves further investigation as a novel treatment for glioma.

【 授权许可】

   
2015 Xu et al.; licensee BioMed Central.

【 图 表 】

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