HDAC inhibition prevents NF-kappa B activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes I kappa B alpha.
HDAC inhibition prevents NF-kappa B activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes I kappa B alpha.
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发表时间：
2005
影响因子：
5.8
通讯作者：
R. Place;E. Noonan;C. Giardina
中科院分区：
文献类型：
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作者：
R. Place;E. Noonan;C. Giardina
短链脂肪酸(SCFA)、丁酸(BA)和其他组蛋白脱乙酰酶(HDAC)抑制剂可迅速诱导结肠癌细胞系细胞周期停滞和分化。我们发现丁酸盐和特定的HDAC抑制剂曲古抑素A(TSA)可以重新编程结肠癌细胞中的核因子-(Kappa)B反应。具体地说，在丁酸分化的细胞中，肿瘤坏死因子-α的激活受到抑制，而IL-1β的激活在很大程度上不受影响。为了深入了解丁酸诱导分化与核因子-(Kappa)B调控之间的关系，我们确定了丁酸对蛋白酶体活性和亚单位表达的影响。有趣的是，丁酸盐和TSA降低了结肠癌细胞系中细胞蛋白酶体的活性。蛋白酶体活性的下降是由于蛋白酶体催化β亚基在蛋白质和mRNA水平上的表达减少所致。HDAC抑制剂对肿瘤坏死因子-α诱导的核因子-(KappaB)B激活的选择性影响似乎与以下事实有关：肿瘤坏死因子-α诱导的核因子-(KappaB)B的激活是由蛋白酶体介导的，而IL-1β对核因子-kappaB的激活在很大程度上是不依赖于蛋白酶体的。这些发现表明，细胞分化状态和/或增殖能力可以显著影响蛋白酶体的活性，并选择性地改变结肠癌细胞中的核因子-(Kappa)B反应。这一信息可能有助于HDAC抑制剂作为抗肿瘤和抗炎药物的进一步开发和靶向。
The short chain fatty acid (SCFA) butyrate (BA) and other histone deacetylase (HDAC) inhibitors can rapidly induce cell cycle arrest and differentation of colon cancer cell lines. We found that butyrate and the specific HDAC inhibitor trichostatin A (TSA) can reprogram the NF-(kappa)B response in colon cancer cells. Specifically, TNF-alpha activation is suppressed in butyrate-differentiated cells, whereas IL-1beta activation is largely unaffected. To gain insight into the relationship between butyrate-induced differentiation and NF-(kappa)B regulation, we determined the impact of butyrate on proteasome activity and subunit expression. Interestingly, butyrate and TSA reduced the cellular proteasome activity in colon cancer cell lines. The drop in proteasome activity results from the reduced expression of the catalytic beta-type subunits of the proteasome at both the protein and mRNA level. The selective impact of HDAC inhibitors on TNF-alpha-induced NF-(kappa)B activation appears to relate to the fact that the TNF-alpha-induced activation of NF-(kappa)B is mediated by the proteasome, whereas NF-kappaB activation by IL-1beta is largely proteasome-independent. These findings indicate that cellular differentation status and/or proliferative capacity can significantly impact proteasome activity and selectively alter NF-(kappa)B responses in colon cancer cells. This information may be useful for the further development and targeting of HDAC inhibitors as anti-neoplastic and anti-inflammatory agents.