Targeting Epigenetic 'Readers' with Natural Compounds for Cancer Interception.
Targeting Epigenetic 'Readers' with Natural Compounds for Cancer Interception.
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DOI：
10.15430/jcp.2020.25.4.189
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发表时间：
2020-12-30
影响因子：
2.5
通讯作者：
Dashwood RH
中科院分区：
文献类型：
--
作者：
Damiani E;Duran MN;Mohan N;Rajendran P;Dashwood RH
来自不同来源的天然化合物，包括植物和常用的食品和饮料，通过在疾病发病过程中影响表观基因组和基因表达的机制，对健康产生有益的影响。通过瞄准所谓的表观遗传“读者”、“作者”和“擦除器”，饮食植物化学物质可以逆转癌细胞和癌前阶段的异常表观基因组特征。因此，这些药物提供了通过预防或治疗/治疗策略拦截癌症的途径。到目前为止，饮食制剂的大部分注意力都集中在编写者(例如，组蛋白乙酰转移酶)和擦除器(例如，组蛋白去乙酰基酶)上，而较少关注表观遗传读取器(例如，BRD蛋白)。药物JQ1是作为表观遗传阅读器抑制剂的原型开发的，选择性地针对溴域和端外域(BET)家族的成员，如BRD4。将JQ1作为单一药物或与标准护理治疗相结合的临床试验显示出抗肿瘤效果，但并不是没有毒性或耐药性。在追求第二代表观遗传阅读器抑制剂的过程中，人们的注意力已经转移到自然来源上，包括可能被重新用于‘JQ1类’生物活性的饮食制剂。本文综述了天然化合物作为BET和其他表观遗传‘Reader’蛋白的抑制剂的新兴研究活动的现状，并展望了未来的方向和机会。
Natural compounds from diverse sources, including botanicals and commonly consumed foods and beverages, exert beneficial health effects via mechanisms that impact the epigenome and gene expression during disease pathogenesis. By targeting the so-called epigenetic ‘readers’, ‘writers’, and ‘erasers’, dietary phytochemicals can reverse abnormal epigenome signatures in cancer cells and preneoplastic stages. Thus, such agents provide avenues for cancer interception via prevention or treatment/therapeutic strategies. To date, much of the focus on dietary agents has been directed towards writers (e.g., histone acetyltransferases) and erasers (e.g., histone deacetylases), with less attention given to epigenetic readers (e.g., BRD proteins). The drug JQ1 was developed as a prototype epigenetic reader inhibitor, selectively targeting members of the bromodomain and extraterminal domain (BET) family, such as BRD4. Clinical trials with JQ1 as a single agent, or in combination with standard of care therapy, revealed antitumor efficacy but not without toxicity or resistance. In pursuit of second-generation epigenetic reader inhibitors, attention has shifted to natural sources, including dietary agents that might be repurposed as ‘JQ1-like’ bioactives. This review summarizes the current status of nascent research activity focused on natural compounds as inhibitors of BET and other epigenetic ‘reader’ proteins, with a perspective on future directions and opportunities.