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首页> 外文期刊>Molecular and Cellular Biology >Histone Deacetylase Inhibitors Reduce Steroidogenesis through SCF-Mediated Ubiquitination and Degradation of Steroidogenic Factor 1 (NR5A1)
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Histone Deacetylase Inhibitors Reduce Steroidogenesis through SCF-Mediated Ubiquitination and Degradation of Steroidogenic Factor 1 (NR5A1)

机译：组蛋白脱乙酰基酶抑制剂通过SCF介导的泛素化和类固醇生成因子1（NR5A1）的降解减少类固醇生成。

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Histone deacetylase (HDAC) inhibitors such as trichostatin A and valproic acid modulate transcription of many genes by inhibiting the activities of HDACs, resulting in the remodeling of chromatin. Yet this effect is not universal for all genes. Here we show that HDAC inhibitors suppressed the expression of steroidogenic gene CYP11A1 and decreased steroid secretion by increasing the ubiquitination and degradation of SF-1, a factor important for the transcription of all steroidogenic genes. This was accompanied by increased expression of Ube2D1 and SKP1A, an E2 ubiquitin conjugase and a subunit of the E3 ubiquitin ligase in the Skp1/Cul1/F-box protein (SCF) family, respectively. Reducing SKP1A expression with small interfering RNA resulted in recovery of SF-1 levels, demonstrating that the activity of SCF E3 ubiquitin ligase is required for the SF-1 degradation induced by HDAC inhibitors. Overexpression of exogenous SF-1 restored steroidogenic activities even in the presence of HDAC inhibitors. Thus, increased SF-1 degradation is the cause of the reduction in steroidogenesis caused by HDAC inhibitors. The increased SKP1A expression and SCF-mediated protein degradation could be the mechanism underlying the mode of action of HDAC inhibitors.
机译：组蛋白脱乙酰基酶（HDAC）抑制剂，例如曲古抑菌素A和丙戊酸，通过抑制HDAC的活性来调节许多基因的转录，从而导致染色质的重塑。然而，这种效应并非对所有基因都普遍。在这里，我们显示HDAC抑制剂通过增加SF-1的泛素化和降解来抑制类固醇生成基因 CYP11A1 的表达，并减少类固醇分泌，SF-1是所有类固醇生成基因转录的重要因素。这与分别在Skp1 / Cul1 / F-box蛋白（SCF）家族中的Ube2D1和SKP1A，E2泛素结合酶和E3泛素连接酶的亚基的表达增加有关。用小的干扰RNA降低SKP1A表达可导致SF-1水平恢复，表明HDAC抑制剂诱导的SF-1降解需要SCF E3泛素连接酶的活性。即使存在HDAC抑制剂，外源SF-1的过表达也恢复了类固醇生成活性。因此，增加的SF-1降解是由HDAC抑制剂引起的类固醇生成减少的原因。 SKP1A表达增加和SCF介导的蛋白降解可能是HDAC抑制剂作用方式的基础。

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