Negative modulation of the epigenetic regulator, UHRF1, by thyroid hormone receptors suppresses liver cancer cell growth.

Abstract

The thyroid hormone, 3,3',5-triiodo-l-thyronine (T3 ), mediates several physiological processes, including embryonic development, cellular differentiation, metabolism and regulation of cell proliferation. Thyroid hormone (T3 ) and its receptor (TR) are involved in metabolism and growth. In addition to their developmental and metabolic functions, TRs play a tumor suppressor role, and therefore, their aberrant expression can lead to tumor transformation. Aberrant epigenetic silencing of tumor suppressor genes promotes cancer progression. The epigenetic regulator, Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), is overexpressed in various cancers. In our study, we demonstrated that T3 negatively regulates UHRF1 expression, both in vitro and in vivo. Our results further indicate that UHRF1 regulation by T3 is indirect and mediated by Sp1. Sp1-binding elements of UHRF1 were identified at positions -664/-505 of the promoter region using the luciferase and chromatin immunoprecipitation assays. Notably, UHRF1 and Sp1 levels were elevated in subgroups of hepatocellular carcinoma patients and inversely correlated with TRα1 expression. Knockdown of UHRF1 expression should therefore provide a means to inhibit hepatoma cell proliferation. Expression of UHRF1 was downregulated by TRs, in turn, relieving silencing of the UHRF1 target gene, p21. Based on the collective findings, we propose that T3 /TR signaling induces hepatoma cell growth inhibition via UHRF1 repression.

• Authors: Sheng-Ming Wu, Wan-Li Cheng, Chia-Jung Liao, Hsiang-Cheng Chi, Yang-Hsiang Lin, Yi-Hsin Tseng, Chung-Ying Tsai, Ching-Ying Chen, Syuan-Ling Lin, Wei-Jan Chen, Yung-Hsin Yeh, Chi-Ying F Huang, Ming-Huang Chen, Yi-Chen Yeh, Kwang-Huei Lin
• Journal: International journal of cancer (Int J Cancer) Vol. 137 Issue 1 Pg. 37-49 (Jul 01 2015) ISSN: 1097-0215 [Electronic] United States
• PMID: 25430639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 UICC.

Chemical References

• CCAAT-Enhancer-Binding Proteins
• Receptors, Thyroid Hormone
• Sp1 Transcription Factor
• Sp1 protein, human
• Triiodothyronine
• UHRF1 protein, human
• Ubiquitin-Protein Ligases

Topics

• Animals
• CCAAT-Enhancer-Binding Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Hep G2 Cells
• Humans
• Liver Neoplasms (metabolism, pathology)
• Male
• Promoter Regions, Genetic (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Thyroid Hormone (metabolism)
• Sp1 Transcription Factor (metabolism)
• Triiodothyronine (pharmacology)
• Ubiquitin-Protein Ligases