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J. Biol. Chem., Vol. 280, Issue 42, 35477-35489, October 21, 2005

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Pc2-mediated Sumoylation of Smad-interacting Protein 1 Attenuates Transcriptional Repression of E-cadherin^*

Jianyin Long, Dongmei Zuo, and Morag Park, Recipient of a Canadian Institute of Health Research senior scientist award¶||1

From the Molecular Oncology Group, Departments of Biochemistry, ^¶Medicine, and ^||Oncology, McGill University, Montréal, Québec H3A 1A1, Canada

Epithelial-mesenchymal transition (EMT) is important in embryonic development and tumorigenesis. Smad-interacting protein 1 (SIP1) can induce EMT by repressing the transcription of E-cadherin through recruitment of the corepressor C-terminal-binding protein (CtBP). How the activity of SIP1 is regulated still remains unclear. Here we show in vivo and in vitro that SIP1 is covalently modified by sumoylation at two conserved sites, Lys³⁹¹ and Lys⁸⁶⁶. The polycomb protein Pc2, but not the PIAS (protein inhibitor of activated STAT) family proteins, acts as a Small ubiquitin-like modifier E3 ligase for SIP1. Sumoylation of SIP1 does not affect its subcellular localization, but regulates its transcriptional activity. Compared with the wild-type, a SIP1 sumoylation null mutant shows more potent repression on E-cadherin transcription but similar repression on two transforming growth factor--responsive reporter genes and comparable activation on vitamin D3 receptor transcription. Coexpression of SIP1 with Pc2 can partially relieve E-cadherin repression by SIP1. We further show that SIP1 sumoylation disrupts the recruitment of CtBP. Thus SIP1 sumoylation regulates its transcriptional activity in a promoter context-dependent manner and may represent an important intervention target to modulate EMT in tumorigenesis.

Received for publication, April 25, 2005 , and in revised form, July 25, 2005.

^* This work was supported in part by a research grant (to M. P.) from the Canadian Breast Cancer Research Alliance. 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: McGill University Health Centre, 687 Pine Ave. West, Montréal, Québec H3A 1A1, Canada. Tel.: 514-934-1934 (ext. 35845); Fax: 514-843-1478; E-mail: morag.park{at}mcgill.ca.

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