Adamantyl-substituted retinoid-related molecules bind small heterodimer partner and modulate the Sin3A repressor.
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.
Farhana
Lulu
L
John D. Dingell Veterans Affairs Medical Center, 4646 John R. Street, Detroit, MI 48201, USA.
Dawson
Marcia I
MI
Leid
Mark
M
Wang
Li
L
Moore
David D
DD
Liu
Gang
G
Xia
Zeben
Z
Fontana
Joseph A
JA
D000218:Adamantane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000378:metabolism* / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009281:Naphthalenes / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex
C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; C488107:6-(3'-(1-adamantyl)-4'-hydroxyphenyl)-5-chloronaphthalenecarboxylic acid; D002934:Cinnamates; D018841:HSP90 Heat-Shock Proteins; C489427:MYC protein, human; D009281:Naphthalenes; D016271:Proto-Oncogene Proteins c-myc; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C099713:nuclear receptor subfamily 0, group B, member 2; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000251:Adenosine Triphosphatases; D000218:Adamantane