We previously found that the adamantyl-substituted retinoid-related molecules bind to the small heterodimer partner (SHP) as well as the Sin3A complex. In this report, we delineated the role of SHP and the Sin3A complex in 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC)-mediated inhibition of cell growth and apoptosis. We examined the effect of loss of SHP and Sin3A expression in a number of cell types on 3-Cl-AHPC-mediated growth inhibition and apoptosis induction, 3-Cl-AHPC-mediated nuclear factor-kappaB (NF-kappaB) activation, and 3-Cl-AHPC-mediated increase in c-Fos and c-Jun expression. We found that loss of SHP or Sin3A expression, while blocking 3-Cl-AHPC-mediated apoptosis, had little effect on 3-Cl-AHPC inhibition of cellular proliferation. We have previously shown that 3-Cl-AHPC-mediated NF-kappaB activation is necessary for apoptosis induction. We have now shown that 3-Cl-AHPC-enhanced c-Fos and c-Jun expression is also essential for maximal 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC induction of c-Fos and c-Jun expression as well as NF-kappaB activation was dependent on SHP protein levels. In turn, SHP levels are regulated by Sin3A because ablation of Sin3A resulted in a decrease in SHP expression. Thus, SHP and Sin3A play an important role in adamantyl-substituted retinoid-related induction of cellular apoptosis.