Negative modulation of the epigenetic regulator, UHRF1, by thyroid hormone receptors suppresses liver cancer cell growth. Issue 1 (10th December 2014)

• Record Type: Journal Article
• Authors: Wu, Sheng‐Ming; Cheng, Wan‐Li; Liao, Chia‐Jung; Chi, Hsiang‐Cheng; Lin, Yang‐Hsiang; Tseng, Yi‐Hsin; Tsai, Chung‐Ying; Chen, Ching‐Ying; Lin, Syuan‐Ling; Chen, Wei‐Jan; Yeh, Yung‐Hsin; Huang, Chi‐Ying F.; Chen, Ming‐Huang; Yeh, Yi‐Chen; Lin, Kwang‐Huei
• Is Part Of: International journal of cancer. Volume 137:Issue 1(2015:Jul. 01)
• Page Start: 37
• Page End: 49
• Publication Date: 2014-12-10
• Subjects: thyroid hormone receptor -- tumor suppressor -- negatively regulation -- UHRF1 -- hepatocellular carcinoma; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.29368
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? How does the thyroid hormone T3 regulate liver cancer? Here the author show that T3 together with its receptor negatively regulates the expression of the ubiquitin‐like with PHD and ring‐finger domains 1 (UHRF1), an epigenetic regulator overexpressed in various cancers. Because UHRF1 is overexpressed in subgroups of patients with liver cancer and thyroid hormone receptor levels are inversely correlated, the authors propose that T3 and its receptor suppress hepatoma cell growth via suppression of UHRF1 expression.