Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A.
Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A.
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DOI：
10.1186/s13148-017-0359-x
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发表时间：
2017
影响因子：
5.7
通讯作者：
Ghantous A
中科院分区：
文献类型：
--
作者：
Halaburková A;Jendželovský R;Kovaľ J;Herceg Z;Fedoročko P;Ghantous A
金丝桃素介导的光动力疗法（HY-PDT）最近作为一种替代的微创抗癌治疗方法引起了越来越多的关注，尽管癌细胞可能会产生耐药性。因此，联合治疗可能是必要的，以提高HY-PDT疗效。组蛋白脱乙酰酶抑制剂（HDACis）由于其非遗传毒性特性和使细胞对外部刺激敏感的表观遗传潜力而经常用于组合治疗。因此，本研究首次尝试研究HDACis与可见光介导的PDT组合对癌症的治疗效果。具体地，由于其已知对HY-PDT的抗性，使用结肠直肠癌细胞模型。HDACis的两个化学基团与HY-PDT组合测试：异羟肟酸Saha和曲古抑菌素A，以及短链脂肪酸丙戊酸和苯丁酸钠（NaPB），分别作为所有类别与核HDAC的抑制剂。所选HDACis表现出良好的临床毒性特征，并在组内比较中显示出相似的效力和机制，但在组间分析中显示出不同的生物学效应。HDACi与HY-PDT的组合显著减弱了癌细胞对治疗的抗性，并导致两个HDACi组变得相似有效。然而，与HY-PDT组合的短链脂肪酸显示出对HDACs抑制的选择性增加，而不是其他关键的表观遗传酶，NaPB诱导了否则沉默的肿瘤抑制因子CDKN 1A的最强表达，CDKN 1A是HDACi介导的染色质调节的标志基因。NaPB对CDKN 1A的表观遗传调控与增强子和启动子元件处的组蛋白乙酰化有关，而与该基因的这些或其他调控区域处的组蛋白或DNA甲基化无关。此外，与其他HDACis相比，NaPB对整体组蛋白乙酰化的影响较轻，表明相对于整体染色质结构，NaPB对CDKN 1A染色质结构的影响更特异。NaPB + HY-PDT的机制是P53依赖性的，并且可能由HY-PDT而不是NaPB组分驱动。我们的研究结果表明，HDACis增强了HY-PDT在结直肠癌细胞中的抗肿瘤功效，克服了它们对这种药物的耐药性，并在表观遗传学上重新激活了CDKN 1A的表达。除了它们的治疗潜力之外，金丝桃素和这些HDACis是膳食剂的非遗传毒性成分，因此，代表了研究基于膳食的癌症预防机制的有趣目标。本文的在线版本（doi：10.1186/s13148-017-0359-x）包含补充材料，可供授权用户使用。
Hypericin-mediated photodynamic therapy (HY-PDT) has recently captured increased attention as an alternative minimally invasive anticancer treatment, although cancer cells may acquire resistance. Therefore, combination treatments may be necessary to enhance HY-PDT efficacy. Histone deacetylase inhibitors (HDACis) are often used in combination treatments due to their non-genotoxic properties and epigenetic potential to sensitize cells to external stimuli. Therefore, this study attempts for the first time to investigate the therapeutic effects of HDACis in combination with visible light-mediated PDT against cancer. Specifically, the colorectal cancer cell model was used due to its known resistance to HY-PDT. Two chemical groups of HDACis were tested in combination with HY-PDT: the hydroxamic acids Saha and Trichostatin A, and the short-chain fatty acids valproic acid and sodium phenylbutyrate (NaPB), as inhibitors of all-class versus nuclear HDACs, respectively. The selected HDACis manifest a favorable clinical toxicity profile and showed similar potencies and mechanisms in intragroup comparisons but different biological effects in intergroup analyses. HDACi combination with HY-PDT significantly attenuated cancer cell resistance to treatment and caused the two HDACi groups to become similarly potent. However, the short-chain fatty acids, in combination with HY-PDT, showed increased selectivity towards inhibition of HDACs versus other key epigenetic enzymes, and NaPB induced the strongest expression of the otherwise silenced tumor suppressor CDKN1A, a hallmark gene for HDACi-mediated chromatin modulation. Epigenetic regulation of CDKN1A by NaPB was associated with histone acetylation at enhancer and promoter elements rather than histone or DNA methylation at those or other regulatory regions of this gene. Moreover, NaPB, compared to the other HDACis, caused milder effects on global histone acetylation, suggesting a more specific effect on CDKN1A chromatin architecture relative to global chromatin structure. The mechanism of NaPB + HY-PDT was P53-dependent and likely driven by the HY-PDT rather than the NaPB constituent. Our results show that HDACis potentiate the antitumor efficacy of HY-PDT in colorectal cancer cells, overcoming their resistance to this drug and epigenetically reactivating the expression of CDKN1A. Besides their therapeutic potential, hypericin and these HDACis are non-genotoxic constituents of dietary agents, hence, represent interesting targets for investigating mechanisms of dietary-based cancer prevention. The online version of this article (doi:10.1186/s13148-017-0359-x) contains supplementary material, which is available to authorized users.