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J. Biol. Chem., Vol. 282, Issue 37, 26725-26739, September 14, 2007

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v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex^*

From the Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263

SSeCKS (Src-suppressed C kinase substrate), also called gravin/AKAP12, is a large scaffolding protein with metastasis suppressor activity. Two major isoforms of SSeCKS are expressed in most cell and tissue types under the control of two independent promoters, designated and , separated by 68 kb. SSeCKS transcript and protein levels are severely decreased in Src- and Ras-transformed fibroblasts and in many epithelial tumors. By dissecting its promoters with progressive deletion analysis, we identified the sequence between –106 and –49 in the proximal promoter as the minimal v-Src-responsive element, which contains E- and GC-boxes bound by USF1 and Sp1/Sp3, respectively. Both E- and GC-boxes are crucial for v-Src-responsive and basal promoter activities. v-Src does not alter USF1 binding levels at the E-box, but it increases Sp1/Sp3 binding to the GC-box despite no change in their cellular protein abundance. SSeCKS and transcript levels in v-Src/3T3 cells can be restored by treatment with the histone deacetylase inhibitor, trichostatin A, but not with the DNA demethylation agent, 5-azacytidine. Chromatin changes are found only on the promoter even though the proximal promoter contains a similar E- and GC-box arrangement. Recruitment of HDAC1 is necessary and sufficient to cause repression of proximal promoter activity, and the addition of Sp1 and/or Sp3 potentiates the repression. Our data suggest that suppression of the promoter is facilitated by Src-induced changes in the promoter chromatinization mediated by a USF1-Sp1-Sp3 complex.

Received for publication, April 4, 2007 , and in revised form, June 6, 2007.

^* This work was supported by National Institutes of Health Grant CA94108 and Department of Defense Grant PC040256 (to I. H. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14209. Tel.: 716-845-7681; Fax: 716-845-2342; E-mail: Irwin.gelman{at}roswellpark.org.

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