Epigenetic inhibition of nuclear receptor small heterodimer partner is associated with and regulates hepatocellular carcinoma growth

Gastroenterology. 2008 Mar;134(3):793-802. doi: 10.1053/j.gastro.2008.01.006. Epub 2008 Jan 10.


Background & aims: Aberrant hypermethylation of promoter regions in cytosine-guanine dinucleotides (CpG) islands has been shown to be associated with transcriptional silencing of tumor-suppressor genes in many cancers. This study evaluated the methylation profile and the tumor-suppressive function of the small heterodimer partner (SHP, NR0B2) in the development of human hepatocellular carcinoma (HCC).

Methods: Human HCC pathologic specimens and cell lines were used as model systems in this study.

Results: The expression of SHP is diminished in HCC pathologic specimens and cell lines by epigenetic silencing owing to SHP promoter hypermethylation. In vitro methylation decreased SHP promoter transactivation and nuclear receptor LRH-1 binding, an event that was reversed by demethylation. Overexpression of SHP inhibited HCC foci formation, arrested HCC tumor growth in xenografted nude mice, and increased the sensitivity of HCC cells to apoptotic stimuli. Further analysis of a total of 19 normal liver and 57 HCC specimens showed that down-regulation of SHP gene expression may be a common denominator of HCC.

Conclusions: We propose that SHP functions as a novel tumor suppressor in the development of HCC. These findings provide new insight into the molecular mechanisms leading to this common cancer and may have both diagnostic and therapeutic applications.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / prevention & control
  • Cell Line, Tumor
  • CpG Islands
  • DNA Methylation*
  • DNA-Binding Proteins / metabolism
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing*
  • Genetic Therapy / methods
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Time Factors
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Transfection
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays


  • DNA-Binding Proteins
  • NR5A2 protein, human
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Tumor Suppressor Proteins
  • nuclear receptor subfamily 0, group B, member 2