Inhibition of histone deacetylases in melanomaa perspective from bench to bedside
Inhibition of histone deacetylases in melanomaa perspective from bench to bedside
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DOI：
10.1111/exd.13089
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发表时间：
2016-11-01
影响因子：
3.6
通讯作者：
Berking, Carola
中科院分区：
文献类型：
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作者：
Hornig, Eva;Heppt, Markus V.;Berking, Carola
组蛋白脱乙酰酶(HDAC)通过改变DNA的染色质状态，在表观遗传基因调控中发挥重要作用。HDAC和组蛋白乙酰转移酶之间的异常表达、酶活性的失调或失衡可能参与了癌症的发生和发展。HDAC的药理抑制在一组恶性肿瘤中显示出强大的抗肿瘤活性，如结肠癌、胃癌和多发性骨髓瘤。本文综述了HDAC在黑色素瘤中的研究现状，并从实验和临床的角度评价了HDAC抑制的应用。HDACs的分子功能可分为组蛋白作用和非组蛋白作用，在细胞增殖、细胞周期进展和细胞凋亡中具有不同的意义。HDAC抑制可导致细胞周期停滞于G1期，诱导细胞凋亡，增强黑色素瘤细胞的免疫原性。一些研究认为，HDAC抑制可能会克服黑色素瘤细胞对BRAF抑制的耐药性。最近在I期和II期早期试验中测试了几种抑制剂，如涡旋止血药、内生止血药和丙戊酸，但大多数药物作为单一药物显示出有限的有效性和耐受性。HDAC抑制最常见的不良事件包括血液学毒性、疲劳、恶心和实验室异常。现有证据支持HDAC抑制剂(HDACi)可能使黑色素瘤细胞对免疫治疗和靶向治疗增敏的假说，因此在免疫检查点阻断或BRAF和MEK抑制的同时具有治疗潜力。
Histone deacetylases (HDACs) are critically involved in epigenetic gene regulation through alterations of the chromatin status of DNA. Aberrant expression, dysregulation of their enzymatic activity or imbalances between HDACs and histone acetyltransferases are likely involved in the development and progression of cancer. Pharmacologic inhibition of HDACs shows potent antitumor activity in a panel of malignancies such as colon or gastric cancer and multiple myeloma. In this review, we summarize the current knowledge of HDACs in melanoma and evaluate the application of HDAC inhibition from an experimental and clinical perspective. The molecular functions of HDACs can be classified into histone and non-histone effects with diverse implications in proliferation, cell cycle progression and apoptosis. HDAC inhibition results in G1 cell cycle arrest, induces apoptosis and increases the immunogenicity of melanoma cells. Some studies proposed that HDAC inhibition may overcome the resistance of melanoma cells to BRAF inhibition. Several inhibitors such as vorinostat, entinostat and valproic acid have recently been tested in phase I and early phase II trials, yet most agents show limited efficacy and tolerability as single agents. The most frequent adverse events of HDAC inhibition comprise haematological toxicity, fatigue, nausea and laboratory abnormalities. Existing evidence supports the hypothesis that HDAC inhibitors (HDACi) may sensitize melanoma cells to immunotherapy and targeted therapy and hence bear therapeutic potential concurrent with immune checkpoint blockade or BRAF and MEK inhibition.