Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation.
Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation.
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DOI：
10.1038/ki.2011.296
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发表时间：
2012-01
影响因子：
19.6
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中科院分区：
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在 Pkd2 敲除小鼠（常染色体显性多囊肾病 (ADPKD) 模型）中，发现全组蛋白脱乙酰酶 (HDAC) 抑制剂曲古抑菌素 A 可以减少囊肿进展并减缓肾功能下降。在这里，我们确定 HDAC 抑制作用是通过调节细胞增殖以防止囊肿形成，还是通过其他机制发挥作用。 Pkd1 的缺失导致转录调节因子分化抑制剂 2 (Id2) 上调，从而在体外突变小鼠胚胎肾细胞中触发 Id2 介导的 p21 下调。使用 Pkd1 突变体小鼠胚胎肾细胞，我们发现曲古抑菌素 A 降低了 Id2，从而导致 p21 上调。此外，这些细胞中通常受 Cdk2/Cdk4 活性调节的磷酸化视网膜母细胞瘤 (Rb) 也有所减少。由于后面这些酶受 p21 控制，这些研究表明曲古抑菌素 A 减少的囊肿上皮细胞增殖可能是由于 p21 上调或通过 Rb-E2F 途径引起的。其他研究表明，Id2 直接与 Rb 结合，从转录失活的 Rb-E2F 复合物中释放转录激活剂 E2F。 HDAC 抑制能够通过下调 Id2 来逆转这一过程。此外，用曲古抑菌素 A 治疗怀孕的 Pkd1 小鼠可防止发育中的胚胎肾脏中囊肿的形成，表明这种抑制在早期囊肿形成期间在体内是有效的。因此，HDAC 抑制作用针对 Id2 介导的途径，下调囊性上皮细胞增殖，从而下调囊肿发生。
The pan-histone deacetylase (HDAC) inhibitor, trichostatin A, was found to reduce cyst progression and slow the decline of kidney function in Pkd2 knockout mice, model of autosomal dominant polycystic kidney disease (ADPKD). Here we determine whether HDAC inhibition acts by regulating cell proliferation to prevent cyst formation, or by other mechanisms. The loss of Pkd1 caused an upregulation of the inhibitor of differentiation 2 (Id2), a transcription regulator, triggering an Id2-mediated downregulation of p21 in mutant mouse embryonic kidney cells in vitro. Using mouse embryonic kidney cells, mutant for Pkd1, we found that trichostatin A decreased Id2, which resulted in upregulation of p21. Further, phosphorylated retinoblastoma (Rb), usually regulated by Cdk2/Cdk4 activity, was also reduced in these cells. Since these latter enzymes are under the control of p21, these studies suggest that the proliferation of cyst epithelial cells that is reduced by trichostatin A might result from p21 upregulation, or alternatively through the Rb-E2F pathway. Additional studies showed that Id2 directly bound to Rb, releasing the transcription activator E2F from transcriptionally inactive Rb-E2F complexes. HDAC inhibition was able to reverse this process by downregulation of Id2. Furthermore, treatment of pregnant Pkd1 mice with trichostatin A prevented cyst formation in the developing embryonic kidneys, showing that this inhibition is effective in vivo during early cyst formation. Thus, HDAC inhibition targets Id2-mediated pathways to downregulate cystic epithelial cell proliferation and hence cystogenesis.
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