New Insights into Orphan Nuclear Receptor SHP in Liver Cancer

Small heterodimer partner (SHP; NR0B2) is a unique orphan nuclear receptor (NR) that contains a putative ligand-binding domain but lacks a DNA-binding domain. SHP is a transcriptional corepressor affecting diverse metabolic processes including bile acid synthesis, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology via interaction with multiple NRs and transcriptional factors (TFs). Hepatocellular carcinoma (HCC) is one of the most deadly human cancers worldwide with few therapeutic options and poor prognosis. Recently, it is becoming clear that SHP plays an antitumor role in the development of liver cancer. In this review, we summarize the most recent findings regarding the new SHP interaction partners, new structural insights into SHP's gene repressing activity, and SHP protein posttranslational modifications by bile acids. We also discuss the pleiotropic role of SHP in regulating cell proliferation, apoptosis, DNA methylation, and inflammation that are related to antitumor role of SHP in HCC. Improving our understanding of SHP's antitumor role in the development of liver cancer will provide new insights into developing novel treatments or prevention strategies. Future research will focus on developing more efficacious and specific synthetic SHP ligands for pharmaceutical applications in liver cancer and several metabolic diseases such as hypercholesterolemia, obesity, diabetes, and fatty liver disease.