Abstract
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.
Highlights
Nuclear receptors (NRs) constitute a large family of transcription factors (TFs) that govern a wide array of cellular activities in development, metabolism, and physiology
Hepatocellular carcinoma (HCC) development is linked to the metabolic disease as both increased cancer risk and worsened cancer outcome have been observed in metabolic syndrome and nonalcoholic fatty liver disease [10]
The fact that small heterodimer partner (SHP) acts as a critical transcriptional corepressor in diverse metabolic processes provides potential means to develop SHP-targeted therapeutics for metabolic diseases
Summary
Nuclear receptors (NRs) constitute a large family of transcription factors (TFs) that govern a wide array of cellular activities in development, metabolism, and physiology. SHP inhibits numerous NRs and TFs in diverse metabolic pathways including bile acid synthesis, Nuclear Receptor Research cholesterol and lipid metabolism, glucose metabolism, and energy homeostasis [2,3,4,5,6,7,8]. HCC development is linked to the metabolic disease as both increased cancer risk and worsened cancer outcome have been observed in metabolic syndrome and nonalcoholic fatty liver disease [10]. Recent studies showed that SHP plays an antitumor role in the development of liver cancer. We summarize the most recent findings regarding the new SHP interaction partners, new structural insights into how SHP represses gene transcription, and SHP protein posttranslational modifications (PTMs) mediated by bile acids. An increased understanding of tumor suppressor function of SHP in the development of liver cancer will provide critical knowledge to improve the diagnostic, therapeutic, or preventive strategies for liver cancer
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