Makki Mohammad Shahidul, Heinzel Thorsten, Englert Christoph
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
Nucleic Acids Res. 2008 Jul;36(12):4067-78. doi: 10.1093/nar/gkn356. Epub 2008 Jun 4.
The Wilms tumor gene WT1 encodes a zinc-finger transcription factor that is inactivated in a subset of pediatric kidney cancers. During embryogenesis, WT1 is expressed in a time- and tissue-specific manner in various organs including gonads and kidney but also in the hematopoietic system. Although widely regarded as a tumor suppressor gene, wild-type WT1 is overexpressed in a variety of hematologic malignancies, most notably in acute lymphoblastic leukemia as well as myelodysplastic syndromes. Reduction of WT1 expression levels leads to decrease of proliferation and apoptosis of leukemic cells, suggesting that in certain contexts WT1 might act as an oncogene. We show here that histone deacetylase inhibitors like Trichostatin A (TSA) can promptly and dramatically downregulate Wt1 expression levels in different cell lines. This effect was mostly due to the cessation of transcription and was mediated by sequences located in intron 3 of Wt1. In addition, TSA also caused enhanced degradation of the Wt1 protein by the proteasome. This was at least in part due to induction of the ubiquitin-conjugating enzyme UBCH8. Thus, downregulation of Wt1 expression might contribute to the beneficial effects of histone deacetylase inhibitors that are currently used in clinical trials as cancer therapeutics.
威尔姆斯瘤基因WT1编码一种锌指转录因子，该因子在一部分儿童肾癌中失活。在胚胎发育过程中，WT1在包括性腺、肾脏以及造血系统在内的各种器官中以时间和组织特异性的方式表达。尽管WT1被广泛认为是一种肿瘤抑制基因，但野生型WT1在多种血液系统恶性肿瘤中过度表达，最显著的是在急性淋巴细胞白血病以及骨髓增生异常综合征中。WT1表达水平的降低导致白血病细胞增殖和凋亡减少，这表明在某些情况下WT1可能作为一种癌基因发挥作用。我们在此表明，像曲古抑菌素A（TSA）这样的组蛋白去乙酰化酶抑制剂能够迅速且显著地下调不同细胞系中Wt1的表达水平。这种效应主要是由于转录的停止，并且由位于Wt1第3内含子中的序列介导。此外，TSA还导致蛋白酶体对Wt1蛋白的降解增强。这至少部分是由于泛素结合酶UBCH8的诱导。因此，Wt1表达的下调可能有助于目前在癌症治疗临床试验中使用的组蛋白去乙酰化酶抑制剂的有益效果。
