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Molecular and Cellular Biology, October 2007, p. 7284-7290, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00476-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Histone Deacetylase Inhibitors Reduce Steroidogenesis through SCF-Mediated Ubiquitination and Degradation of Steroidogenic Factor 1 (NR5A1){triangledown}

Wei-Yi Chen,1,{dagger} Jui-Hsia Weng,1,2 Chen-Che Huang,1,{ddagger} and Bon-chu Chung1,2*

Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan,1 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan2

Received 20 March 2007/ Returned for modification 20 April 2007/ Accepted 2 August 2007

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.

* Corresponding author. Mailing address: Institute of Molecular Biology, 48, Academia Sinica, 128 Academia Road Section 2, Nankang, Taipei 115, Taiwan. Phone: 886-2-2789 9215. Fax: 886-2-2782 6085. E-mail: mbchung{at}sinica.edu.tw

{triangledown} Published ahead of print on 20 August 2007.

{dagger} Present address: Laboratory of Biochemistry and Molecular Biology, Rockefeller University, 1230 York Avenue, New York, NY 10021.

{ddagger} Present address: Department of Veterinary Biosciences, University of Illinois at Urbana Champaign, 2001 S Lincoln Avenue, Urbana, IL 61802-6178.

Molecular and Cellular Biology, October 2007, p. 7284-7290, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00476-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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