Increased protein processing gene signature in HDACi-resistant cells predicts response to proteasome inhibitors.
Increased protein processing gene signature in HDACi-resistant cells predicts response to proteasome inhibitors.
复制标题
HDACi 抗性细胞中蛋白质加工基因特征的增加预示着对蛋白酶体抑制剂的反应。
DOI：
10.1080/10428194.2016.1180684
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发表时间：
2017
影响因子：
2.6
通讯作者：
Assoulin
中科院分区：
文献类型：
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作者：
Dupéré-Richer,Daphné;Kinal,Mena;Pettersson,Filippa;Emond,Audrey;Calvo-Vidal,MNieves;Nichol,JessicaN;Guilbert,Cynthia;Plourde,Dany;KleinOros,Kathleen;Nielsen,TorstenH;Ezponda,Teresa;Licht,JonathanD;Johnson,NathalieA;Assoulin
组蛋白去乙酰化酶抑制剂（HDACi）作为单药的客观缓解率范围为5.5%至49%[1-5]。此外，HDACi以不同的方式发挥其抗肿瘤作用，在给定的癌症或患者中可能具有不同的重要性（在[6]中综述）。确定哪些患者将从含HDACi的治疗中受益仍未解决。然而，有证据表明HDACi用作化疗增敏剂时疗效更好。[7]例如，使用表观遗传药物与常规治疗，如放射和蒽环类药物，显着增加体外和体内癌细胞死亡。[8]通过分析HDACi耐药细胞，我们鉴定了那些细胞的基因表达特征，这些细胞尽管对HDACi诱导的细胞毒性有抗性，但对随后的靶向药物有反应，为了确定与HDACi耐药相关的基因表达变化，我们询问了我们的HDACi耐药模型，伏立诺他耐药U937细胞。[9]这些细胞对伏立诺他具有抗性，并且还对泛HDACi LBH 589（帕比司他）和HDAC 6抑制剂tubastatin具有交叉抗性。[9]我们使用暴露于和不暴露于伏立诺他12小时的亲本U937细胞的cDNA微阵列进行全基因组表达分析，抗性U937-B8细胞在伏立诺他中连续生长，并且U937-B8细胞在没有药物的情况下生长一周。表达谱分析和其他方法在补充方法（可在线获得）中描述。特别地，我们比较了以下细胞之间的基因表达：（1）U937-B8细胞和亲本U937细胞，（2）在伏立诺他存在（U937-B8）或不存在（U937-B8一周洗脱）的情况下，和（3）在有和没有短期（12小时）暴露于伏立诺他的情况下，U937-B8细胞和亲本U937细胞的基因表达。
Histone deacetylase inhibitors (HDACi) have modest objective response rates ranging from 5.5% to 49%[1–5] as single agents. Furthermore, HDACi exert their antitumor effects in different ways, likely of varying importance in a given cancer or patient (reviewed in [6]). Identifying the patients who will benefit from HDACi-containing therapy remains unresolved. However, there is evidence for greater efficacy when HDACi are used as a chemo-sensitizer.[7] For example, using epigenetic drugs alongside conventional therapy, such as radiation and anthracyclines, significantly increases cancer cell death in vitro and in vivo.[8] By profiling HDACi-resistant cells, we identified a gene expression signature of those cells that were ‘primed’to respond to subsequent targeted agents, despite being resistant to HDACi-induced cytotoxicity.To define gene expression changes associated with HDACi resistance, we interrogated our model of HDACiresistance, vorinostat-resistant U937 cells.[9] These cells are resistant to vorinostat, and are also cross-resistant to the pan-HDACi LBH589 (panobinostat) and the HDAC6 inhibitor tubastatin.[9] We performed whole genome expression analyses using cDNA microarrays of parental U937 cells with and without a 12h exposure to vorinostat, the resistant U937-B8 cells grown continuously in vorinostat and U937-B8 cells grown one week without the drug. Expression profiling and other methods are described in the Supplementary Methods (available online). In particular, we compared gene expression between:(1) U937-B8 cells and parental U937 cells,(2) in the presence (U937-B8) or not of vorinostat (U937-B8 one week wash off), and (3) with and without short-term (12 h) exposure to vorinostat in