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Adamantyl-Substituted Retinoid-Related Molecules Bind Small Heterodimer Partner and Modulate the Sin3A Repressor

¹ John D. Dingell Veterans Affairs Medical Center and Department of Medicine, Wayne State University and Karmanos Cancer Institute, Detroit, Michigan; ² Burnham Institute, La Jolla, California; ³ Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon; ⁴ Department of Medicine and Pharmacology, The University of Kansas Medical Center, Kansas City, Kansas; and ⁵ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas

Requests for reprints: Joseph A. Fontana, John D. Dingell Veterans Affairs Medical Center, Oncology 11M-HO, 4646 John R. Street, Detroit, MI 48201. Phone: 313-576-3659; Fax: 313-576-1122; E-mail: Joseph.Fontana{at}va.gov.

6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) and 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) are inducers of apoptosis of malignant cells both in vitro and in vivo. Numerous mechanisms have been proposed for how these compounds exert this effect. This report shows that AHPN/3-Cl-AHPC binds specifically to the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), and this binding promotes interaction of the receptor with a corepressor complex that minimally contains Sin3A, N-CoR, histone deacetylase 4, and HSP90. Formation of the SHP-Sin3A complex is essential for the ability of AHPN and 3-Cl-AHPC to induce apoptosis, as both knockout SHP and knockdown of Sin3A compromise the proapoptotic activity of these compounds but not other apoptosis inducers. These results suggest that AHPN/3-Cl-AHPC and their analogues are SHP ligands and their induction of apoptosis is mediated by their binding to the SHP receptor. [Cancer Res 2007;67(1):318–25]

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