Department of Pathology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
BMC Med Genomics. 2009 Nov 30;2:67. doi: 10.1186/1755-8794-2-67.
Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes.
HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity Pathway Analysis.
Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed.
This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.
尽管在结肠癌化疗方面取得了重大进展，但晚期疾病仍基本无法治愈，迫切需要新的有效化疗药物。组蛋白去乙酰化酶抑制剂（HDACi）是一类新型药物，具有良好的临床前活性，正在结肠癌的临床评估中。本研究的目的是鉴定两种临床先进的羟肟酸 HDACi（伏立诺他和 LBH589）在结肠癌细胞中差异调控的基因，为新的药物联合治疗提供依据，并鉴定一组核心的 HDACi 调控基因。
用 LBH589 或伏立诺他处理 HCT116 和 HT29 结肠癌细胞，采用 MTS、Western blot 和流式细胞术分析药物处理后细胞生长抑制、乙酰化状态和细胞凋亡的变化。此外，还采用 Illumina Human-6 V2 BeadChip 芯片和 Ingenuity 通路分析进行基因表达分析。
伏立诺他或 LBH589 处理可迅速诱导组蛋白乙酰化、细胞周期停滞，并抑制 HCT116 和 HT29 细胞的生长。在每个细胞系中，用两种所测试的 HDACi 处理后，微阵列分析的生物信息学分析显示出在表达改变的基因方面具有显著的相似性。然而，对在 HCT116 和 HT29 细胞中表达改变的基因进行分析显示，HDACi 处理存在细胞系特异性反应。此外，在分析的两种结肠癌细胞系中均鉴定出由伏立诺他和 LBH589 共同调节的 11 个核心基因。
本研究鉴定了 HDACi 诱导的参与核苷酸代谢、血管生成、有丝分裂和细胞存活的关键基因的改变，这些改变可能代表结肠癌新的治疗联合的潜在干预点。这些信息将有助于确定 HDACi 调节的新途径和靶标，为 HDACi 的作用机制提供急需的信息，并为新的药物联合治疗提供依据。我们鉴定了一个由伏立诺他和 LBH589 以相似方式共同调节的 11 个核心基因，这些核心基因将有助于开发和验证一个共同的基因集，该基因集可能代表结肠癌中 HDAC 抑制的分子特征。
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