1. Molecular Mechanism of the Cell Death Induced by the Histone Deacetylase Pan Inhibitor LBH589 (Panobinostat) in Wilms Tumor Cells
- Author
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Su Guang-Hao, Xu Li-Xiao, Liu Lin, Zhu Xue-ming, Fang Fang, Hu Shao-Yan, Xiao Pei-Fang, Li Zhi-Heng, Jin Mei-fang, Ni Jian, Du Xiao-Juan, Cao Lan, Wang Jian, Xu Yun-Yun, Lu Jun, Tao Yan-Fang, Wu Yi, Li Yan-Hong, Zhou Hui-Ting, Zhao He, Feng Xing, Li Yi-Ping, Zhao Wen-Li, Wang Na-Na, Li Gang, Pan Jian, and Sun Lichao
- Subjects
Indoles ,Mice, Nude ,lcsh:Medicine ,Apoptosis ,Hydroxamic Acids ,Wilms Tumor ,Mice ,chemistry.chemical_compound ,Cell Line, Tumor ,Panobinostat ,medicine ,Animals ,Humans ,Cancer epigenetics ,lcsh:Science ,Cell Proliferation ,Histone deacetylase 5 ,Multidisciplinary ,biology ,HDAC11 ,fungi ,lcsh:R ,Wilms' tumor ,medicine.disease ,Xenograft Model Antitumor Assays ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Histone Deacetylase Inhibitors ,Gene Ontology ,Histone ,chemistry ,Acetylation ,biology.protein ,RNA, Long Noncoding ,lcsh:Q ,Histone deacetylase ,Research Article - Abstract
Background Wilms tumor (WT) is an embryonic kidney cancer, for which histone acetylation might be a therapeutic target. LBH589, a novel targeted agent, suppresses histone deacetylases in many tumors. This study investigated the antitumor activity of LBH589 in SK-NEP-1 and G401 cells. Methods SK-NEP-1 and G401 cell growth was assessed by CCK-8 and in nude mice experiments. Annexin V/propidium iodide staining followed by flow cytometry detected apoptosis in cell culture. Gene expressions of LBH589-treated tumor cells were analyzed using an Arraystar Human LncRNA Array. The Multi Experiment View cluster software analyzed the expression data. Differentially expressed genes from the cluster analyses were imported into the Ingenuity Pathway Analysis tool. Results LBH589 inhibited cell proliferation of SK-NEP-1 and G401 cells in a dose-dependent manner. Annexin V, TUNEL and Hochest 33342 staining analysis showed that LBH589-treated cells showed more apoptotic features compared with the control. LBH589 treatment inhibited the growth of SK-NEP-1 xenograft tumors in nude mice. Arraystar Human LncRNA Array analysis of genes and lncRNAs regulated by LBH589 identified 6653 mRNAs and 8135 lncRNAs in LBH589-treated SK-NEP-1 cells. The most enriched gene ontology terms were those involved in nucleosome assembly. KEGG pathway analysis identified cell cycle proteins, including CCNA2, CCNB2, CCND1, CCND2, CDK4, CDKN1B and HDAC2, etc. Ingenuity Pathway Analysis identified important upstream molecules: HIST2H3C, HIST1H4A, HIST1A, HIST1C, HIST1D, histone H1, histone H3, RPRM, HSP70 and MYC. Conclusions LBH589 treatment caused apoptosis and inhibition of cell proliferation of SK-NEP-1and G401 cells. LBH589 had a significant effect and few side effects on SK-NEP-1 xenograft tumors. Expression profiling, and GO, KEGG and IPA analyses identified new targets and a new “network” of genes responding to LBH589 treatment in SK-NEP-1 cells. RPRM, HSP70 and MYC may be important regulators during LBH589 treatment. Our results provide new clues to the proapoptotic mechanism of LBH589.
- Published
- 2015