Adenovirus-mediated expression of UHRF1 reduces the radiosensitivity of cervical cancer HeLa cells to γ-irradiation

Li, Xinli; Meng, Qinghui; Fan, Saijun

doi:10.1038/aps.2009.18

Cited by 23 publications

(19 citation statements)

References 21 publications

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“…Similarly, knockdown of UHRF1 in HEK293 and WI-38 cells also renders these cells hypersensitive to X rays, UV light, and hydroxyurea (14). More recently, UHRF1 has also been shown to facilitate the DNA damage response (DDR) to gamma irradiation (15,16). Consistently, DNA damage results in a decrease in the UHRF1 mRNA as well as protein level (1).…”

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confidence: 62%

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

Chen

Inuzuka

et al. 2013

Molecular and Cellular Biology

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f UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) is a critical epigenetic player involved in the maintenance of DNA methylation patterns during DNA replication. Dysregulation of the UHRF1 level is implicated in cancer onset, metastasis, and tumor recurrence. Previous studies demonstrated that UHRF1 can be stabilized through USP7-mediated deubiquitylation, but the mechanism through which UHRF1 is ubiquitylated is still unknown. Here we show that proteasomal degradation of UHRF1 is mediated by the SCF ␤-TrCP E3 ligase. Through bioinformatic and mutagenesis studies, we identified a functional DSG degron in the UHRF1 N terminus that is necessary for UHRF1 stability regulation. We further show that UHRF1 physically interacts with ␤-TrCP1 in a manner dependent on phosphorylation of serine 108 (S108 UHRF1 ) within the DSG degron. Furthermore, we demonstrate that S108 UHRF1 phosphorylation is catalyzed by casein kinase 1 delta (CK1␦) and is important for the recognition of UHRF1 by SCF ␤-TrCP . Importantly, we demonstrate that UHRF1 degradation is accelerated in response to DNA damage, coincident with enhanced S108 UHRF1 phosphorylation. Taken together, our data identify SCF ␤-TrCP as a bona fide UHRF1 E3 ligase important for regulating UHRF1 steady-state levels both under normal conditions and in response to DNA damage.T he epigenetic regulator UHRF1 is composed of multiple functional domains, including the UBL, Tudor, PHD, SRA, and RING domains, which are responsible for the recognition of histone and DNA methylation as well as ubiquitylation by UHRF1. These domains underlie the ability of UHRF1 to play a role in multiple processes, such as maintenance of DNA methylation, heterochromatin organization, and gene transcription (1-8). Previous studies identified a correlation between UHRF1 overexpression and cancer progression and metastasis, possibly through silencing of various tumor suppressor genes (9-12). Moreover, UHRF1 is implicated in apoptosis in response to DNA damage. Murine embryonic stem cells with targeted disruption of the Uhrf1 gene are hypersensitive to DNA-damaging agents (13). Similarly, knockdown of UHRF1 in HEK293 and WI-38 cells also renders these cells hypersensitive to X rays, UV light, and hydroxyurea (14). More recently, UHRF1 has also been shown to facilitate the DNA damage response (DDR) to gamma irradiation (15, 16). Consistently, DNA damage results in a decrease in the UHRF1 mRNA as well as protein level (1). More recent studies suggest that UHRF1 turnover is controlled by proteasome-mediated degradation. These studies identified the deubiquitylase USP7 in the regulation of the UHRF1 level in vivo (17-19). Specifically, UHRF1 is protected from proteasome-mediated degradation through its association with the deubiquitylase USP7, in a cell cycle-dependent manner. At the M phase of the cell cycle, USP7 disassociates from UHRF1, thus exposing UHRF1 to proteasomal degradation (18). Importantly, manipulating the UHRF1 level in cells has been shown to affect cell proliferation (11,18,20...

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confidence: 62%

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

Chen

Inuzuka

et al. 2013

Molecular and Cellular Biology

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“…Furthermore, significant overexpression of UHRF1 has been observed in several types of human tumor, including breast (13,14), bladder (15), prostate (16) and lung cancer (17). 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).…”

Section: Introductionmentioning

confidence: 99%

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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“…UHRF1 is an abnormal expression gene, we screened the radiosensitizing drug using gene-chip, in our previous studies on the gene demonstrated that UHRF1 showed significant radioresistance (13,14), and to further explore its biological functions, we performed a series of experiments in breast cancer MDA-MB-231 cells to explore the effect of UHRF1 on proliferation of cells in vitro, growth of nude mice in vivo and the underlying mechanisms, the role of UHRF1 in regulating invasion and migration was also explored.…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact biological functions of UHRF1 are uncertain, previous studies in vitro showed that UHRF1 may be a growth-regulating gene because its expression is regulated during the cell cycle, and it forced post-mitotic cells to proliferate (9,10). The expressions of UHRF1 mRNA and protein were low in quiescent cells and high in proliferating cells and tissues, including breast carcinomas (11), and our previous study also indicated that UHRF1 promoted growth of breast duct cancer BT-549 cells (12), and conferred radioresistance of HeLa cells (13) and breast cancer cells (14), all our results suggested its oncogene traits. However, few studies have explored whether UHRF1 could regulate proliferation in vivo, and affect invasion and migration of breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…The E1-deleted adenovirus-β-gal (Ad-β-gal) was obtained from Invitrogen Therapeutics (Houston, TX, USA). A recombinant adenovirus (pAd/CMV/V5-DEST; Invitrogen) containing a DNA fragment encoding the complete amino acid sequence of human UHRF1 (Ad5-UHRF1) between the CMV promoter and the polyadenylation signal (TK pA) was prepared as previously described (13).…”

Section: Generation Of Uhrf1 Pten and Maspin Expression Plasmidmentioning

confidence: 99%

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Exogenous expression of UHRF1 promotes proliferation and metastasis of breast cancer cells

Nie

et al. 2012

Oncol Rep

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Abstract. In the present study, we investigated the role of UHRF1 (ubiquitin-like protein containing PHD and RING finger domains 1) in proliferation, invasion and migration of breast cancer cells, and the potential mechanisms were also explored. Cell proliferation was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay; cell cycle distribution and apoptosis were evaluated using flow cytometry; protein expression was determined by western blotting; angiogenesis of xenografts was assessed by microvessel density (MVD); cell invasion was measured using transwell chamber; cell migration was determined by wound scratching assay. Our results demonstrated that UHRF1 transfection conferred serum independence to MDA-MB-231 cells, G 1 phase shortage and apoptosis suppression, accompanied with an increased expression of cyclin D 1 and decreased expression of Bax. Significant pro-invasion and pro-migration activity was observed, with no obvious effect on the expression of PTEN and maspin. Co-expression of the UHRF1/PTEN or UHRF1/maspin degraded the role of UHRF1 in regulating invasion and migration. UHRF1 induced growth of MDA-MB-231 cells by promoting tumor vessel formation in vivo. In conclusion, UHRF1 promoted the proliferation of breast cancer cells by apoptosis inhibition, G 1 phase shortage and promotion of tumor vessel formation, and pro-invasion and pro-migration activity was also observed by interacting with PTEN and maspin. Thus, UHRF1 may serve as a new therapy target for breast cancer.

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Adenovirus-mediated expression of UHRF1 reduces the radiosensitivity of cervical cancer HeLa cells to γ-irradiation

Cited by 23 publications

References 21 publications

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

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

Exogenous expression of UHRF1 promotes proliferation and metastasis of breast cancer cells

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Adenovirus-mediated expression of UHRF1 reduces the radiosensitivity of cervical cancer HeLa cells to γ-irradiation

Cited by 23 publications

References 21 publications

DNA Damage Regulates UHRF1 Stability via the SCFβ-TrCP E3 Ligase

DNA Damage Regulates UHRF1 Stability via the SCFβ-TrCP E3 Ligase

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

Exogenous expression of UHRF1 promotes proliferation and metastasis of breast cancer cells

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DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase