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Molecular and Cellular Biology, April 2007, p. 2661-2675, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01098-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

An Acetylation/Deacetylation-SUMOylation Switch through a Phylogenetically Conserved KXEP Motif in the Tumor Suppressor HIC1 Regulates Transcriptional Repression Activity

Nicolas Stankovic-Valentin ,^1,,¶ Sophie Deltour,^1, Jacob Seeler,² Sébastien Pinte,^1, Gérard Vergoten,³ Cateline Guérardel,^1, Anne Dejean,² and Dominique Leprince^1*

CNRS UMR 8526, Institut de Biologie de Lille, Institut Pasteur de Lille, 1 Rue Calmette, BP 447, 59017 Lille Cedex, France,¹ Nuclear Organization and Oncogenesis Unit, INSERM U579, Institut Pasteur, 27 Rue du Dr Roux, 75074 Paris Cedex 15, France,² CNRS UMR 8576, Unité de Glycobiologie Fonctionelle et Structurale, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France³

Received 19 June 2006/ Returned for modification 18 July 2006/ Accepted 16 January 2007

Tumor suppressor HIC1 (hypermethylated in cancer 1) is a gene that is essential for mammalian development, epigenetically silenced in many human tumors, and involved in a complex pathway regulating P53 tumor suppression activity. HIC1 encodes a sequence-specific transcriptional repressor containing five Krüppel-like C₂H₂ zinc fingers and an N-terminal BTB/POZ repression domain. Here, we show that endogenous HIC1 is SUMOylated in vivo on a phylogenetically conserved lysine, K314, located in the central region which is a second repression domain. K314R mutation does not influence HIC1 subnuclear localization but significantly reduces its transcriptional repression potential, as does the mutation of the other conserved residue in the KXE consensus, E316A, or the overexpression of the deSUMOylase SSP3/SENP2. Furthermore, HIC1 is acetylated in vitro by P300/CBP. Strikingly, the K314R mutant is less acetylated than wild-type HIC1, suggesting that this lysine is a target for both SUMOylation and acetylation. We further show that HIC1 transcriptional repression activity is positively controlled by two types of deacetylases, SIRT1 and HDAC4, which increase the deacetylation and SUMOylation, respectively, of K314. Knockdown of endogenous SIRT1 by the transfection of short interfering RNA causes a significant loss of HIC1 SUMOylation. Thus, this dual-deacetylase complex induces either a phosphorylation-dependent acetylation-SUMOylation switch through a KXEXXSP motif, as previously shown for MEF2, or a phosphorylation-independent switch through a KXEP motif, as shown here for HIC1, since P317A mutation severely impairs HIC1 acetylation. Finally, our results demonstrate that HIC1 is a target of the class III deacetylase SIRT1 and identify a new posttranslational modification step in the P53-HIC1-SIRT1 regulatory loop.

Published ahead of print on 5 February 2007.

Present address: CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Lille, France.

^¶ Present address: Department Biochemie I, University of Goettingen, Humbolt Allee 23, 37073 Goettingen, Germany.

Present address: Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom.

Present address: CNRS UMR 5161, Laboratoire de Biologie Moléculaire et Cellulaire, Ecole Normale Supérieure, 46 Allée d'Italie, 69364 Lyon Cedex 07, France.

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