Nuclear receptor small heterodimer partner in apoptosis signaling and liver cancer

Abstract

Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that contains the dimerization and a putative ligand-binding domain, but lacks the conserved DNA binding domain. SHP exerts its physiological function as an inhibitor of gene transcription through physical interaction with multiple nuclear receptors and transcriptional factors. SHP is a critical transcriptional regulator affecting diverse biological functions, including bile acid, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology. Recently, we and others have demonstrated that SHP is an epigenetically regulated transcriptional repressor that suppresses the development of liver cancer. In this review, we summarize recent major findings regarding the role of SHP in cell proliferation, apoptosis, and DNA methylation, and discuss recent progress in understanding the function of SHP as a tumor suppressor in the development of liver cancer. Future study will be focused on identifying SHP associated novel pro-oncogenes and anti-oncogenes in liver cancer progression and applying the knowledge gained on SHP in liver cancer prevention, diagnosis and treatment.

Figure 1.

Role of SHP in apoptosis signaling. SHP is proposed to have both inhibitory and stimulatory effects on apoptosis (depending on cell types). SHP represses apoptosis through inhibiting the transcription of Nur77 and inducing the cytoplasmic sequestration of p21WAF1. SHP activates apoptosis by translocating to mitochondria, binding to the anti-apoptotic protein Bcl-2, and disrupting Bcl-2/Bid interaction to cause cytochrome c release. SHP also activates apoptosis through regulating miR-206 expression to block the anti-apoptotic activity of Notch3. The adamantyl-substituted retinoid-related (ARR) compounds AHPN and 3-Cl-AHPC bind directly to SHP, which promotes the formation of a corepressor complex containing Sin3A, nuclear receptor co-repressor (N-CoR) to activate apoptosis. ARRs also increase SHP protein stability by preventing its degradation and enhance SHP mitochondrial targeting. Activation pathways are shown as blue arrows, and inhibitory pathways are shown as red lines.

Figure 2.

Role of SHP in the development of HCC. The loss of SHP increases hepatocyte proliferation (though cyclinD1), decreases apoptosis (though Bcl2), and results in genome wide epigenetic changes (through Dnmts), including DNA hypomethylation and the hypermethylation of tumor suppressor genes. These events coordinately promote the development of HCC.