Epigenetic alteration of the NF-κB-inducing kinase (NIK) gene is involved in enhanced NIK expression in basal-like breast cancer
Epigenetic alteration of the NF-κB-inducing kinase (NIK) gene is involved in enhanced NIK expression in basal-like breast cancer
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DOI：
10.1111/j.1349-7006.2010.01685.x
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发表时间：
2010-11-01
期刊：
影响因子：
5.7
通讯作者：
Inoue, Jun-ichiro
中科院分区：
文献类型：
--
作者：
Yamamoto, Mizuki;Ito, Taku;Inoue, Jun-ichiro
基底样乳腺癌是一种三阴性肿瘤（雌激素受体阴性，孕激素受体阴性，红母细胞白血病病毒癌基因同源物2 （ERBB2）阴性），具有侵袭性临床行为，缺乏有效的分子靶点治疗。我们之前报道过基底样亚型细胞系表现出高组成核因子(NF)- κ B激活，其在基底样亚型中的抑制抑制了它们的增殖。此外，NF-kappa B诱导激酶（NIK）参与了NF-kappa B的组成性激活。在这里，我们报告了NIK基因的表观遗传改变引起的NIK基因表达增强，这种表达只在基底样亚型中观察到，而不是在发光样亚型或非致瘤性乳腺上皮细胞中观察到。NIK mRNA的稳定性和NIK启动子驱动的转录活性在基底样亚型和发光样亚型中是相似的。然而，在基底样亚型中，组蛋白H3乙酰化水平上调。此外，用组蛋白去乙酰化酶抑制剂丙戊酸处理发光样亚型，可显著增加NIK的表达。虽然没有检测到NIK位点的DNA甲基化，但当luminal-like亚型被5-氮杂胞苷处理时，NIK的表达也增加，5-氮杂胞苷除抑制DNA甲基化外，还抑制组蛋白H3-Lys-9二甲基化。综上所述，这些结果表明，由组蛋白H3甲基化和去乙酰化介导的封闭染色质结构抑制了NIK在光样亚型中的表达，而这些抑制机制的破坏导致NIK表达增强和基底样亚型中组成性NF-kappa B的激活。因此，NIK和由NIK介导的组成型nf - κ B活化诱导的基因可能是基底样乳腺癌的治疗靶点。[j] .癌症科学，2010;01:2391-2397。
Basal-like breast cancers are triple-negative (estrogen receptor negative, progesterone receptor negative, erythroblastic leukemia viral oncogene homolog 2 (ERBB2) negative) tumors with an aggressive clinical behavior that lacks effective molecular targets for therapy. We reported previously that the basal-like subtype cell lines display high constitutive nuclear factor (NF)-kappa B activation, whose inhibition in the basal-like subtypes suppressed their proliferation. Moreover, NF-kappa B-inducing kinase (NIK) is involved in the constitutive NF-kappa B activation. Here, we report that enhanced NIK expression, which is exclusively observed in the basal-like subtype rather than the luminal-like subtype or non-tumorigenic mammary epithelial cells, is caused by epigenetic alteration of the NIK gene. The stability of NIK mRNA and transcriptional activity driven by the NIK promoter are similar in the basal-like and luminal-like subtypes. However, histone H3 acetylation levels were up-regulated in the basal-like subtype. Furthermore, treatment of the luminal-like subtype with a histone deacetylase inhibitor, valproic acid, significantly increased NIK expression. Although DNA methylation of the NIK locus was not detected, NIK expression also increased when the luminal-like subtype was treated with 5-azacytidine, which inhibits histone H3-Lys-9 dimethylation in addition to DNA methylation. Taken together, these results suggest that the closed chromatin structure mediated by histone H3 methylation and deacetylation suppresses NIK expression in the luminal-like subtype, whereas disruption of these suppression mechanisms leads to enhanced NIK expression and the constitutive NF-kappa B activation in the basal-like subtype. Thus, NIK and genes induced by the NIK-mediated constitutive NF-kappa B activation could be therapeutic targets of basal-like breast cancer. (Cancer Sci 2010; 101: 2391-2397).