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

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

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)37-49
Number of pages13
JournalInternational Journal of Cancer
Issue number1
Publication statusPublished - Jul 1 2015
Externally publishedYes


  • hepatocellular carcinoma
  • negatively regulation
  • thyroid hormone receptor
  • tumor suppressor
  • UHRF1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • General Medicine


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