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The molecular mechanism of histone deacetylase inhibitor (HDACi) PCI‐24781 mediating anti‐tumor activity in neuroblastoma cells
Author(s) -
Zhan Qing Lei,
Ngai Sai Ming
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.810.12
Subject(s) - histone deacetylase , neuroblastoma , cancer research , epigenetics , carcinogenesis , histone deacetylase inhibitor , cell cycle , apoptosis , histone , cell growth , cell cycle checkpoint , biology , conventional pci , chemistry , medicine , cell culture , cancer , biochemistry , genetics , gene , myocardial infarction
Neuroblastoma accounts for 7–10% of all childhood cancers, and it is the second most common solid tumor diagnosed during infancy. The survival rate among children with high‐risk neuroblastoma is less than 40%, despite intensive multi‐modality treatment, highlighting the urgent needs for new treatment strategies. Epigenetic changes are known to be important for tumorigenesis and a number of drugs targeting epigenetic regulation have been developed for anticancer therapies. Among those drugs, the most effective ones are histone deacetylase inhibitors (HDACi). Numerous HDACi are currently in phase I/II clinical trials for various tumor types. However, little is known about the role of PCI‐24781, a novel HDACi in nueroblastoma. In the present study, we investigated the underlying mechanisms that mediate anti‐tumor activity of PCI‐24781 in neuroblastoma cell line SK‐N‐DZ. PCI‐24781 treatment inhibited tumor growth at very low doses in SK‐N‐DZ, while normal cell line HS‐68 shown a relatively resistance to treatment. PCI‐24781 caused the accumulation of acetylated histone H3 and cell cycle arrest in G2/M phase in SK‐N‐ DZ. Treatment of SK‐N‐DZ with PCI‐24781 also induced apoptosis signaling pathways via up‐regulating some genes associated with apoptosis, including death receptor DR4, caspase3, p21 and p53. Furthermore, the 2D electrophoresis‐based proteomic analysis revealed different protein expression profile in SK‐N‐DZ cells treated with PCI‐24781 for 24 h and 36 h. The identified proteins involved in many biological processes, including energy metabolism, DNA repair, transcription regulation, cell cycle and proliferation. Immunoblotting analysis further confirmed that PCI‐24781 could increase the expression of prohibitin, hHR23a and RuvB2. These studies will enable a better understanding of molecular mechanisms underlying PCI‐24781‐mediated anti‐tumor effects in neuroblastoma cells SK‐N‐DZ.