NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT.
NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT.
复制标题
DOI：
10.1038/cddis.2014.569
复制
发表时间：
2015-01-22
影响因子：
9
通讯作者：
Bhat-Nakshatri P
中科院分区：
文献类型：
--
作者：
Nakshatri H;Appaiah HN;Anjanappa M;Gilley D;Tanaka H;Badve S;Crooks PA;Mathews W;Sweeney C;Bhat-Nakshatri P
转录因子核因子-kappaB(NF-κB)在多种癌症中具有结构性活性，是治疗发展的靶点。我们最近开发了二甲氨基苯内酯(DMAPT)，这是一种临床级别的巴豆内酯的水溶性类似物，作为一种有效的NF-κB抑制剂，并在体外和体内证明了对多种癌症的抗肿瘤活性。在这项研究中，我们证明了DMAPT是一种表观遗传调节因子，其功能依赖于NF-κB和非依赖于NF-DNA B。DMAPT介导的NF-κB抑制导致组蛋白H3K36三甲基化(H3K36me3)升高，这可能通过基因消融NF-κB的p65亚单位或kappaBα超抑制物过表达来实现。DMAPT处理和P65消融使H3K36三甲基酶NSD1(KMT3B)和SETD2(KMT3A)水平升高，提示NF-κB直接抑制它们的表达，而较低的H3K36me3是结构性NF-κB活性的表观遗传标志。NSD1和H3K36me3基因的高表达降低了NSD1和H3K36me3的水平。NSD1对于DMAPT诱导的促凋亡BIM的表达是必不可少的，这表明表观遗传修饰和基因表达之间存在功能联系。有趣的是，我们观察到在DMAPT处理的细胞中增强了H4K20三甲基化和诱导了H4K20三甲基酶KMT5C，而不依赖于NF-κB的抑制。这些结果将KMT5C添加到菊内酯的NF-κB非依赖性表观遗传靶点列表中，其中包括先前描述的组蛋白脱乙酰基酶1(HDAC-1)和DNA甲基转移酶1。由于NSD1和SETD2是已知的肿瘤抑制因子，并且H4K20三甲基化的缺失是癌症进展中的早期事件，从而导致基因组不稳定，我们建议DMAPT作为一种有效的药理学药物，可以逆转依赖和独立于肿瘤的NF-κB的表观遗传学异常。
The transcription factor nuclear factor-kappaB (NF-κB) is constitutively active in several cancers and is a target of therapeutic development. We recently developed dimethylaminoparthenolide (DMAPT), a clinical grade water-soluble analog of parthenolide, as a potent inhibitor of NF-κB and demonstrated in vitro and in vivo anti-tumor activities in multiple cancers. In this study, we show DMAPT is an epigenetic modulator functioning in an NF-κB-dependent and -independent manner. DMAPT-mediated NF-κB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-κB or inhibitor-of-kappaB alpha super-repressor overexpression. DMAPT treatment and p65 ablation increased the levels of H3K36 trimethylases NSD1 (KMT3B) and SETD2 (KMT3A), suggesting that NF-κB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-κB activity. Overexpression of a constitutively active p65 subunit of NF-κB reduced NSD1 and H3K36me3 levels. NSD1 is essential for DMAPT-induced expression of pro-apoptotic BIM, indicating a functional link between epigenetic modification and gene expression. Interestingly, we observed enhanced H4K20 trimethylation and induction of H4K20 trimethylase KMT5C in DMAPT-treated cells independent of NF-κB inhibition. These results add KMT5C to the list NF-κB-independent epigenetic targets of parthenolide, which include previously described histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1. As NSD1 and SETD2 are known tumor suppressors and loss of H4K20 trimethylation is an early event in cancer progression, which contributes to genomic instability, we propose DMAPT as a potent pharmacologic agent that can reverse NF-κB-dependent and -independent cancer-specific epigenetic abnormalities.