联合抑制组蛋白去乙酰化酶和胞苷脱氨酶可提高地西他滨在结直肠癌中的表观遗传效力。

IF 5.7 2区 医学 Q1 Medicine
Zijiao Tang, Lu Liu, Jürgen Borlak
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引用次数: 1

摘要

背景:靶向癌性疾病的表观基因组是一种创新的方法,DNA甲基化抑制剂地西他滨被推荐用于血液系统恶性肿瘤的治疗。虽然表观遗传改变在实体瘤中也很常见,但地西他滨在结直肠癌(COAD)中的治疗效果并不理想。目前的研究重点是确定联合化疗药物或检查点抑制剂在调节肿瘤微环境中的作用。在这里,我们报告了一系列分子研究,以评估地西他滨,组蛋白去乙酰化酶抑制剂PBA和胞苷脱氨酶抑制剂四氢吡啶(THU)在患者来源的功能性和p53缺失结肠癌细胞系(CCCL)中的效力。我们关注细胞增殖的抑制、肿瘤抑制因子的恢复和程序性细胞死亡,并通过评估270例COAD患者的药物反应基因来建立临床相关性。此外,我们根据CpG岛密度评估了治疗效果。结果:地西他滨明显抑制DNMT1蛋白。相反,PBA处理CCCL恢复了组蛋白3赖氨酸残基的乙酰化,这使得染色质处于开放状态。与单一地西他滨治疗不同,地西他滨/PBA联合治疗对细胞增殖的抑制作用> 95%,阻止细胞周期进展,特别是在S期和g2期,并诱导程序性细胞死亡。地西他滨和PBA促进不同染色体上基因重新表达的能力不同,地西他滨/PBA联合治疗对COAD患者癌症相关基因组区域中40种肿瘤抑制基因和13种典型沉默基因的重新表达最有效。此外,该处理抑制了11个存活(抗凋亡)基因的表达,增强了x染色体失活基因的表达,特别是lncRNA Xist,促进了p53介导的细胞凋亡。THU或其基因敲低对CDA的药理学抑制可防止地西他滨失活。引人注目的是,PBA治疗恢复了地西他滨药物摄取转运体SLC15A1的表达,从而实现了高肿瘤药物负荷。最后,对于26个药物反应基因,我们证明了COAD患者的生存率提高。结论:地西他滨/PBA/THU联合治疗可显著提高药物效力,鉴于其现有的监管批准,我们的研究结果值得对COAD患者进行三联用药的前瞻性临床试验。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas.

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas.

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas.

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas.

Background: Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of hematological malignancies. Although epigenetic alterations are also common to solid tumors, the therapeutic efficacy of decitabine in colorectal adenocarcinomas (COAD) is unfavorable. Current research focuses on an identification of combination therapies either with chemotherapeutics or checkpoint inhibitors in modulating the tumor microenvironment. Here we report a series of molecular investigations to evaluate potency of decitabine, the histone deacetylase inhibitor PBA and the cytidine deaminase (CDA) inhibitor tetrahydrouridine (THU) in patient derived functional and p53 null colon cancer cell lines (CCCL). We focused on the inhibition of cell proliferation, the recovery of tumor suppressors and programmed cell death, and established clinical relevance by evaluating drug responsive genes among 270 COAD patients. Furthermore, we evaluated treatment responses based on CpG island density.

Results: Decitabine caused marked repression of the DNMT1 protein. Conversely, PBA treatment of CCCL recovered acetylation of histone 3 lysine residues, and this enabled an open chromatin state. Unlike single decitabine treatment, the combined decitabine/PBA treatment caused > 95% inhibition of cell proliferation, prevented cell cycle progression especially in the S and G2-phase and induced programmed cell death. Decitabine and PBA differed in their ability to facilitate re-expression of genes localized on different chromosomes, and the combined decitabine/PBA treatment was most effective in the re-expression of 40 tumor suppressors and 13 genes typically silenced in cancer-associated genomic regions of COAD patients. Furthermore, this treatment repressed expression of 11 survival (anti-apoptotic) genes and augmented expression of X-chromosome inactivated genes, especially the lncRNA Xist to facilitate p53-mediated apoptosis. Pharmacological inhibition of CDA by THU or its gene knockdown prevented decitabine inactivation. Strikingly, PBA treatment recovered the expression of the decitabine drug-uptake transporter SLC15A1, thus enabling high tumor drug-loads. Finally, for 26 drug responsive genes we demonstrated improved survival in COAD patients.

Conclusion: The combined decitabine/PBA/THU drug treatment improved drug potency considerably, and given their existing regulatory approval, our findings merit prospective clinical trials for the triple combination in COAD patients.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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