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J. Biol. Chem., Vol. 281, Issue 8, 4718-4725, February 24, 2006

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HER-2/neu Represses the Metastasis Suppressor RECK via ERK and Sp Transcription Factors to Promote Cell Invasion^*

Ming-Chuan Hsu, Hui-Chiu Chang, and Wen-Chun Hung^¶1

From the Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, and ^¶Center of Gene Regulation and Signal Transduction, National Cheng Kung University, Tainan 701, Taiwan

Matrix metalloproteinase (MMP) inhibitory proteins may negatively regulate MMP activity to suppress tumor metastasis. In this study, we demonstrate that the HER-2/neu oncogene inhibits the expression of the MMP inhibitor RECK to promote cell invasion. RECK was inhibited via transcriptional repression in B104-1-1 cells, which express constitutively active HER-2/neu. Overexpression of HER-2/neu in NIH/3T3 or HaCaT cells also suppressed RECK expression. Deletion and mutation assays showed that HER-2/neu repressed RECK via the Sp1-binding site localized in the –82/–71 region from the translational start site. DNA affinity precipitation and chromatin immunoprecipitation assays indicated that binding of Sp1 and Sp3 to this consensus site was increased in B104-1-1 cells. We also found that HER-2/neu inhibited RECK via the ERK signaling pathway. Sp1 proteins phosphorylated at Thr⁴⁵³ and Thr⁷³⁹ by ERK bound preferentially to the RECK promoter, and this binding was reversed by HER-2/neu and ERK inhibitors. Furthermore, our data indicate that HER-2/neu obviously increased HDAC1 binding to the Sp1-binding site localized in the –82/–71 region of the RECK promoter. The histone deacetylase inhibitor trichostatin A reversed HER-2/neu-induced inhibition of RECK. HER-2/neu activation was associated with increased MMP-9 secretion and activation. Re-expression of RECK in HER-2/neu-overexpressing cells inhibited MMP-9 secretion and cell invasion. Taken together, our results suggest that HER-2/neu induces the binding of Sp proteins and HDAC1 to the RECK promoter to inhibit RECK expression and to promote cell invasion. Restoration of RECK provides a novel strategy for the inhibition of HER-2/neu-induced metastasis.

Received for publication, October 6, 2005 , and in revised form, December 23, 2005.

^* This work was supported by Grants NSC-93-2314-B-110-001 and 94-2320-B-110-008 from the National Science Council, Grant 91-B-FA09–1-4 from the Ministry of Education (MOE) Program for Promoting Academic Excellence of Universities, and the University Integration Program for the National Cheng Kung and Sun Yat-Sen Universities from MOE (to W.-C. H.). 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.

¹ To whom correspondence should be addressed: Inst. of Biomedical Sciences, National Sun Yat-Sen University, No. 70, Lien-Hai Rd., Kaohsiung 804, Taiwan. Tel.: 886-7-525-2000; Fax: 886-7-525-0197; E-mail: hung1228{at}ms10.hinet.net.

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