Strategies to re-express epigenetically silenced p15INK4b and p21WAF1 genes in acute myeloid leukemia
Strategies to re-express epigenetically silenced p15INK4b and p21WAF1 genes in acute myeloid leukemia
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DOI：
10.4161/epi.5.8.13276
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发表时间：
2010-11-01
期刊：
影响因子：
3.7
通讯作者：
Geyer, C. Ronald
中科院分区：
文献类型：
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作者：
Geyer, C. Ronald
p15（INK 4 B）和p21（WAF 1）是TGF β靶点，在白血病中通过涉及DNA甲基化和/或组蛋白修饰的表观遗传机制沉默。建立和维持p15（INK 4 B）和p21（WAF 1）的表观遗传沉默的机制尚未完全建立。表观遗传修饰的可逆性导致了靶向DNA甲基转移酶、组蛋白脱乙酰酶和组蛋白甲基转移酶的药物的开发，这些药物已用于重新表达白血病中异常沉默的基因。最近，非编码RNA，被称为天然反义转录物（NAT），已涉及表观遗传修饰的调节。在这里，我们回顾了沉默p15（INK 4 B）和p21（WAF 1）的表观遗传机制以及NAT在这一过程中的作用。我们还回顾了用于重新表达p15（INK 4 B）和p21（WAF 1）的表观遗传药物和药物组合。最后，我们讨论了NAT的潜在用途，以针对特定基因的表观遗传药物的活性，并永久重新表达表观遗传沉默的基因。
p15(INK4B) and p21(WAF1) are TGF beta targets that are silenced in leukemia by epigenetic mechanisms involving DNA methylation and/or histone modifications. Mechanisms for establishing and maintaining epigenetic silencing of p15(INK4B) and p21(WAF1) are not well established. The reversible nature of epigenetic modifications has lead to the development of drugs that target DNA methyltransferases, histone deacetylases and histone methyltransferases, which have been used to re-express aberrantly silenced genes in leukemia. Recently, non-coding RNA, referred to as natural antisense transcripts (NATs), have been implicated in the regulation of epigenetic modifications. Here, we review epigenetic mechanisms for silencing p15(INK4B) and p21(WAF1) and the role of NATs in this process. We also review epigenetic drugs and drug combinations used to re-express p15(INK4B) and p21(WAF1). Lastly, we discuss the potential use of NATs to target the activity of epigenetic drugs to specific genes and to permanently re-express epigenetically silenced genes.