UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma

Mudbhary, Raksha; Hoshida, Yujin; Chernyavskaya, Yelena; Jacob, Vinitha; Villanueva, Augusto; Fiel, M. Isabel; Chen, Xintong; Kojima, Kensuke; Thung, Swan N.; Bronson, Roderick T.; Lachenmayer, Anja; Revill, Kate; Alsinet, Clara; Sachidanandam, Ravi; Desai, Anal; SenBanerjee, Sucharita; Ukomadu, Chinweike; Llovet, Josep M.; Sadler, Kirsten C.

doi:10.1016/j.ccr.2014.01.003

Cited by 273 publications

(320 citation statements)

References 64 publications

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“…UHRF1 has previously been identified as an oncogene in hepatocellular carcinoma (19,20). Furthermore, the overexpression of UHRF1 destabilizes and delocalizes DNMT1, and causes DNA hypomethylation in cancer cells (19). Although several studies have demonstrated the function of UHRF1 in tumorigenesis and tumor progression (14,17,20), little is known regarding the function of UHRF1 in human osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…UHRF1 is overexpressed and associated with tumor stages, and predicts poor prognosis in various types of cancer (15,21). UHRF1 has previously been identified as an oncogene in hepatocellular carcinoma (19,20). Furthermore, the overexpression of UHRF1 destabilizes and delocalizes DNMT1, and causes DNA hypomethylation in cancer cells (19).…”

Section: Discussionmentioning

confidence: 99%

“…The overexpression of UHRF1 has also been reported to reduce the radiosensitivity of human breast cancer cells and HeLa cells to γ-irradiation (18). Previous studies have demonstrated that UHRF1 is an oncogene in hepatocellular carcinoma (19,20 Furthermore, the overexpression of UHRF1 destabilizes and delocalizes DNA (cytosine-5-)-methyltransferase 1 (DNMT1) and causes DNA hypomethylation in cancer cells (19). Despite these findings, little is known regarding the function of UHRF1 in human osteosarcoma cells.…”

Section: Introductionmentioning

confidence: 94%

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UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

Liu

Qiao

Wang

et al. 2015

Molecular Medicine Reports

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Abstract. Ubiquitin-like with plant homeodomain (PHD) and RING-finger domain 1 (UHRF1) maintains methylation patterns following DNA replication and is expressed at high levels in various types of human cancer. UHRF1 has been identified as a novel oncogene involved in the pathogenesis of hepatocellular carcinoma. Previous studies have demonstrated that inhibition of the expression of UHRF1 suppresses the proliferation of cancer cells. However, the role of UHRF1 in human osteosarcoma has not been investigated. The present study examined the expression levels of UHRF1 and retinoblastoma 1 (Rb1) in human osteosarcoma cell lines by western blot analysis. Stable overexpression of UHRF1 or knockdown of Rb1 was achieved by lentiviral transfection. Subsequently, a Cell Counting Kit-8 assay and a cell invasion assay were performed to detect the biological functions of UHRF1 in vitro. The results of the present study demonstrated that UHRF1 promoted the proliferation of human osteosarcoma cells. The present study also reported that UHRF1 was able to enhance the invasion of osteosarcoma cells in a retinoblastoma 1 (Rb1)-dependent manner. UHRF1 promoted invasion in Rb1-positive osteosarcoma cells, but not in Saos-2 cells with homozygous loss of Rb1. Similarly, knockdown of Rb1 in Rb1-positive osteosarcoma cells enhanced levels of invasion and eliminated the regulation of invasion by UHRF1. UHRF1 was found to inhibit the mRNA and protein expression levels of Rb1. Furthermore, deletion of Rb1 was found to suppress the expression of E-cadherin and promote epithelial-to-mesenchymal transition (EMT). In addition, the overexpression of UHRF1 inhibited the expression of E-cadherin and promoted EMT via the suppression of Rb1. These data demonstrated that UHRF1 promotes osteosarcoma cell invasion by downregulating the expression of E-cadherin and increasing EMT in an Rb1-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

Liu

Qiao

Wang

et al. 2015

Molecular Medicine Reports

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“…A primary role of Uhrf1 is to recruit DNMT1 to replicating DNA where it acts to maintain methylation patterns at CpG dinucleotides through replication (28)(29)(30)(31)(32). In vertebrates, promoters with low CpG density acquire DNA methylation during development (33), which has been correlated with repression of transcriptional activity (34) and demonstrated to cause promoter silencing (35).…”

Section: Resultsmentioning

confidence: 99%

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Marjoram¹,

Alvers²,

Deerhake

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

168

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The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.inflammation | Uhrf1 | DNA methylation | tumor necrosis factor | zebrafish I ntestinal epithelial cells (IECs) function as a barrier to prevent luminal contents from accessing underlying tissues, and loss of barrier function is a crucial factor leading to the development of inflammatory bowel diseases (IBD) (1). IBD, including Crohn's disease and ulcerative colitis, are intestinal disorders of poorly understood origin thought to arise from genetic susceptibility, luminal microbiota, immune responses, and environmental factors (2-4). A key element in IBD onset is the up-regulation of the proinflammatory cytokine tumor necrosis factor (TNF) by various cell types including immune cells and IECs. TNF overexpression has been detected in the Paneth cells within the epithelium of human IBD patients (5), and anti-TNF treatments are used successfully to treat patients with Crohn's disease (6). Previous research in mice has demonstrated that intestinal TNF exposure leads to loss of barrier function (7), and overexpression of TNF in mouse IECs is sufficient to elicit an IBD phenotype (8). Despite its pathogenic relevance, the genetic mechanisms regulating TNF expression and IBD onset remain largely unknown.Genome-wide association studies have identified numerous susceptibility loci associated with IBD including ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) and the DNA methyltransferases DNMT1 and DNMT3a (9, 10), which are genes involved in DNA methylation controlling epigenetic transcriptional repression. Moreover, low concordance rates have been observed in monozygotic twin studies (3), leading to the hypothesis that epigenetic regulation also contributes to IBD pathogenesis. Changes in DNA and histone modifications associated with epigenetic regulation have been detected in IBD patients (3, 4, 9, 11, 12), but direct links to the I...

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“…UHRF1 also promotes the activity, specificity and degradation of DNMT1 (Bashtrykov et al, 2014;Berkyurek et al, 2014;Qin et al, 2011). Thus, UHRF1 serves to both promote and restrict DNA methylation and, consequently, both loss (Bostick et al, 2007;Feng et al, 2010;Sharif et al, 2007) and overexpression (Mudbhary et al, 2014) of UHRF1 restructures the methylome.…”

Section: Introductionmentioning

confidence: 99%

DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos

et al. 2015

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UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 to hemimethylated DNA during replication and is essential for maintaining DNA methylation. uhrf1 mutant zebrafish have global DNA hypomethylation and display embryonic defects, including a small liver, and they die as larvae. We make the surprising finding that, despite their reduced organ size, uhrf1 mutants express high levels of genes controlling S-phase and have many more cells undergoing DNA replication, as measured by BrdU incorporation. In contrast to wild-type hepatocytes, which are continually dividing during hepatic outgrowth and thus dilute the BrdU label, uhrf1 mutant hepatocytes retain BrdU throughout outgrowth, reflecting cell cycle arrest. Pulse-chase-pulse experiments with BrdU and EdU, and DNA content analysis indicate that uhrf1 mutant cells undergo DNA re-replication and that apoptosis is the fate of many of the rereplicating and arrested hepatocytes. Importantly, the DNA rereplication phenotype and hepatic outgrowth failure are preceded by global loss of DNA methylation. Moreover, uhrf1 mutants are phenocopied by mutation of dnmt1, and Dnmt1 knockdown in uhrf1 mutants enhances their small liver phenotype. Together, these data indicate that unscheduled DNA replication and failed cell cycle progression leading to apoptosis are the mechanisms by which DNA hypomethylation prevents organ expansion in uhrf1 mutants. We propose that cell cycle arrest leading to apoptosis is a strategy that restricts propagation of epigenetically damaged cells during embryogenesis.

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UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma

Cited by 273 publications

References 64 publications

UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

Epigenetic control of intestinal barrier function and inflammation in zebrafish

DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos

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