Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage
Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage
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DOI：
10.1111/j.1755-148x.2008.00480.x
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发表时间：
2008-08-01
影响因子：
4.3
通讯作者：
Fisher, David E.
中科院分区：
文献类型：
--
作者：
Yokoyama, Satoru;Feige, Erez;Fisher, David E.
黑色素瘤的发病率继续以惊人的速度上升，而有效的系统治疗仍然非常有限。小眼症相关转录因子（MITF）是黑色素细胞发育所必需的，是一种在一部分人黑色素瘤中扩增的癌基因。小眼症相关转录因子也在人类透明细胞肉瘤中发挥致癌作用，透明细胞肉瘤通常表现出黑色素瘤样特征。尽管MITF的药理学抑制在各种临床环境中具有潜在的意义，但尚不清楚其是否含有能够直接抑制小分子的内在催化活性。另一种药物靶向策略是识别和干扰其表达所需的谱系限制机制。在这里，我们报告了多种组蛋白去乙酰化酶（HDAC）抑制剂药物有效地抑制黑素细胞，黑色素瘤和透明细胞肉瘤细胞中的MITF表达。尽管HDAC抑制剂可能影响许多细胞靶点，但我们观察到局部药物应用对皮肤色素沉着的抑制以及体外和小鼠异种移植物中抗黑色素瘤疗效的证据。因此，HDAC抑制剂药物是在靶向影响黑素细胞谱系的病症中发挥治疗作用的候选药物。
Melanoma incidence continues to rise at an alarming rate while effective systemic therapies remain very limited. Microphthalmia-associated transcription factor (MITF) is required for development of melanocytes and is an amplified oncogene in a fraction of human melanomas. Microphthalmia-associated transcription factor also plays an oncogenic role in human clear cell sarcomas, which typically exhibit melanoma-like features. Although pharmacologic suppression of MITF is of potential interest in a variety of clinical settings, it is not known to contain intrinsic catalytic activity capable of direct small molecule inhibition. An alternative drug-targeting strategy is to identify and interfere with lineage-restricted mechanisms required for its expression. Here, we report that multiple histone deacetylase (HDAC)-inhibitor drugs potently suppress MITF expression in melanocytes, melanoma and clear cell sarcoma cells. Although HDAC inhibitors may affect numerous cellular targets, we observed suppression of skin pigmentation by topical drug application as well as evidence of anti-melanoma efficacy in vitro and in mouse xenografts. Consequently, HDAC inhibitor drugs are candidates to play therapeutic roles in targeting conditions affecting the melanocyte lineage.