title: Targeted inhibition of HDAC8 increases the doxorubicin sensitivity of neuroblastoma cells via up regulation of miR-137.
abstract: Histone deacetylases (HDACs) have been suggested to be potential therapeutic targets for cancer treatment. Recent studies revealed that HDAC8 expression was associated with poor prognostic markers and poor overall survival rate of neuroblastoma (NB). Our present study revealed that among the four members of class I HDACs, HDAC8 is significantly over expressed in NB cells as compared with the normal fibroblast 3T3 cells or primary normal human astrocytes (NHA) cells. Targeted inhibition of HDAC8 by its specific siRNA (si-HDAC8) can inhibit the in vitro growth of NB cells. Furthermore, si-HDAC8 significantly increases the sensitivity of NB cells to doxorubicin (Dox). Silencing of HDAC8 can increase the expression of miR-137, which has been suggested to mediate the Dox sensitivity of NB cells. Knockdown of miR-137 can attenuate si-HDAC8 enhanced Dox sensitivity. Further, si-HDAC8 can also inhibit the expression of multi-drug resistance gene 1 (MDR1). While knockdown of miR-137 can attenuate si-HDAC8 induced down regulation of MDR1. Collectively, our data revealed that targeted inhibition of HDAC8 can suppress the growth of NB cells and increase Dox sensitivity via up regulation of miR-137 and suppression of MDR1. Therefor, combination of HDAC8 inhibitor will be helpful to elevate the treatment outcome of NB patients.
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China. Electronic address: hongminbai@126.com.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Bai
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
authors.forename: Tiandong
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
authors.forename: Fanghe
authors.initials: F
authors.lastname: Gong
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
authors.forename: Jinchong
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of PLA, Liuhua Road, Guangzhou 510010, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D056572:Histone Deacetylase Inhibitors; C545567:MIRN137 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D004317:Doxorubicin; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: Dox; HDAC8; MDR1; MiR-137; Neuroblastoma