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

Abstract

The thyroid hormone, 3,3 0 ,5-triiodo-L-thyronine (T 3 ), mediates several physiological processes, including embryonic development, cellular differentiation, metabolism and regulation of cell proliferation. Thyroid hormone (T 3 ) 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 T 3 negatively regulates UHRF1 expression, both in vitro and in vivo. Our results further indicate that UHRF1 regulation by T 3 is indirect and mediated by Sp1. Sp1-binding elements of UHRF1 were identified at positions 2664/2505 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 TRa1 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 T 3 /TR signaling induces hepatoma cell growth inhibition via UHRF1 repression.The thyroid hormone, 3,3 0 ,5-triiodo-L-thyronine (T 3 ), is an important regulator of several physiological processes, including embryonic development, cellular differentiation, proliferation and metabolism. 1 The actions of T 3 are mediated by nuclear thyroid hormone receptors (TRs), ligand-dependent transcription factors that comprise modular functional domains mediating hormone binding (ligands), DNA binding, receptor homodimerization and heterodimerization and interactions with other transcription factors and cofactors. 2 TRs normally act by binding, generally as heterodimers with the retinoid X receptor, to thyroid hormone response elements located in regulatory regions of target genes. 3 Using cDNA microarray, we previously showed that the Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) oncogene is negatively regulated by T 3 in a TRa1-overexpressing hepatoma cell line. 4 Accumulating evidence supports an association of aberrant TR regulation or mutation of TR genes with human neoplasia. 5 Lin et al. 6 identified truncated TRa1 and TRb1 cDNA fragments in 53% of human hepatocellular carcinomas (HCCs). Moreover, high frequency of multiple point mutations in TRs was observed (89 and 46% for TRa1 and TRb1, respectively). 6 Many of these mutant TRs exhibited loss of T 3 binding and aberrant DNA binding activity. Accumulating evidence has revealed that the thyroid hormone receptor is a potent suppressor of tumorigenesis, invasiveness and metastasis formation. 1 In mammals, DNA methylation plays a crucial role in regulation of gene e...

Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

“…T3 binds to TR regulating the expression of various genes including those involved in cell proliferation [103]. In this context, it has been shown that T3 negatively regulates the expression of UHRF1 in hepatoma cell line, which highly overexpresses TRα1 [104]. UHRF1 was shown to be overexpressed in liver cancer patients and its overexpression was accompanied with the size of tumor [104].…”

“…In this context, it has been shown that T3 negatively regulates the expression of UHRF1 in hepatoma cell line, which highly overexpresses TRα1 [104]. UHRF1 was shown to be overexpressed in liver cancer patients and its overexpression was accompanied with the size of tumor [104]. Exposure of TR-expressing HepG2 cells to T3 decreased the levels of UHRF1 mRNA and protein compared to TR-muted HepG2 [104].…”

“…UHRF1 was shown to be overexpressed in liver cancer patients and its overexpression was accompanied with the size of tumor [104]. Exposure of TR-expressing HepG2 cells to T3 decreased the levels of UHRF1 mRNA and protein compared to TR-muted HepG2 [104]. T3-induced UHRF1 downregulation was associated with a decreased level of the transcription factor Sp1, upregulation of p21, G0/G1 cell cycle arrest and cell proliferation inhibition [104].…”

“…Exposure of TR-expressing HepG2 cells to T3 decreased the levels of UHRF1 mRNA and protein compared to TR-muted HepG2 [104]. T3-induced UHRF1 downregulation was associated with a decreased level of the transcription factor Sp1, upregulation of p21, G0/G1 cell cycle arrest and cell proliferation inhibition [104]. Interestingly, DNA ChIP assay showed that Sp1 binds to a specific site on UHRF1 promoter indicating that T3 regulates the expression of UHRF1 through the transcription factor Sp1 [104].…”

UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation

“…31 Moreover, UHRF1 promotes proliferation and progression in many cancers, including colorectal, 8,9 bladder cancer 32 and liver cancer. 13,33 These results indicate that overexpression of UHRF1 is closely associated with tumor proliferation. Thus, we speculate that UHRF1 may enhance GC cell proliferation and tumorigenesis.…”