Histone deacetylase inhibitors reduce steroidogenesis through SCF-mediated ubiquitination and degradation of steroidogenic factor 1 (NR5A1).
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.
Chen
Wei-Yi
WY
Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan.
Weng
Jui-Hsia
JH
Huang
Chen-Che
CC
Chung
Bon-Chu
BC
D000302:Adrenal Cortex / Q000166:cytology; D000818:Animals; D002460:Cell Line; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*; D025801:Ubiquitin / Q000378:metabolism*; D014635:Valproic Acid / Q000378:metabolism
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D054339:Steroidogenic Factor 1; D013256:Steroids; D025801:Ubiquitin; C012589:trichostatin A; D014635:Valproic Acid; D002786:Cholesterol Side-Chain Cleavage Enzyme; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases
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