title: 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.affiliation: Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Sheng-Ming
authors.initials: SM
authors.lastname: Wu
authors.forename: Wan-Li
authors.initials: WL
authors.lastname: Cheng
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Liao
authors.forename: Hsiang-Cheng
authors.initials: HC
authors.lastname: Chi
authors.forename: Yang-Hsiang
authors.initials: YH
authors.lastname: Lin
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Tseng
authors.forename: Chung-Ying
authors.initials: CY
authors.lastname: Tsai
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Chen
authors.forename: Syuan-Ling
authors.initials: SL
authors.lastname: Lin
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Chen
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.forename: Chi-Ying F
authors.initials: CY
authors.lastname: Huang
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Yeh
authors.forename: Kwang-Huei
authors.initials: KH
authors.lastname: Lin
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D011988:Receptors, Thyroid Hormone; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D014284:Triiodothyronine; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: UHRF1; hepatocellular carcinoma; negatively regulation; thyroid hormone receptor; tumor suppressor