UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer

Jin, Wei; Chen, Li; Chen, Ying; Xu, Si; Di, Gen-Hong; Yin, Wen; Wu, Jiong; Shao, Zhi Ming

doi:10.1007/s10549-009-0652-2

Cited by 99 publications

(83 citation statements)

References 32 publications

(28 reference statements)

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“…This is also supported by findings in breast tumors, where UHRF1 overexpression was correlated with BRCA1 promoter hypermethylation. 33 To provide additional support to our ex vivo observations, we knocked down the expression of UHRF1 in A549 lung adenocarcinoma cell line. Both UHRF1 knockdown derived clones demonstrated reduced methylation of RASSF1, CYGB, and CDH13 promoters, which are hypermethylated in A549.…”

Section: Discussionmentioning

confidence: 88%

“…32 Despite the importance of UHRF1 function in DNA methylation, the current data regarding its contribution to the epigenetic silencing of TSGs in primary human tumors are limited to a single report associating UHRF1 overexpression with BRCA1 promoter methylation in sporadic breast cancer. 33 In this study, we examined the mRNA expression profile of UHRF1 as well as DNMT1, DNMT3A, and DNMT3B in NSCLC and examined their relationship to the methylation status of CDKN2A and RASSF1 gene promoters. In addition, we further investigated the role of UHRF1 in regional hypermethylation by knocking its expression down in a lung cancer cell line.…”

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confidence: 99%

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UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

Daskalos

Oleksiewicz

Filia

et al. 2010

Cancer

108

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BACKGROUND:The UHRF1 gene possesses an essential role in DNA methylation maintenance, but its contribution to tumor suppressor gene hypermethylation in primary human cancers currently remains unclear. METHODS: mRNA expression levels of UHRF1, DNMT1, DNMT3A, DNMT3B, and E2F1 were evaluated in 105 primary nonsmall cell lung carcinomas by quantitative polymerase chain reaction. The methylation status of CDKN2A and RASSF1 promoters was examined by pyrosequencing. UHRF1 was knocked down by short hairpin RNA in A549 lung adenocarcinoma cells. RESULTS: All 4 genes were overexpressed in a coordinated manner in the lung tumor tissues, and their expression correlated with that of E2F1. Higher UHRF1 expression in tumor tissues correlated with the hypermethylation of CDKN2A (P ¼ .005) and RASSF1 promoters (P ¼ .034), and the relationship with a combined epigenotype was even stronger (P ¼ 2.3 Â 10 À4 ). When UHRF1 was knocked down in A549 lung adenocarcinoma cells, lower methylation levels of RASSF1, CYGB, and CDH13 promoters were observed. Also, UHRF1 knockdown clones demonstrated reduced proliferation and decreased cell migration properties. CONCLUSIONS: Our data demonstrate that UHRF1 is a key epigenetic switch, which controls cell cycle in nonsmall cell lung carcinoma through its ability to sustain the transcriptional silencing of tumor suppressor genes by maintaining their promoters in a hypermethylated status. Thus, UHRF1 should be considered, along with DNMTs, among the potential targets for cancer treatment and/or therapeutic stratification.

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Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

Daskalos

Oleksiewicz

Filia

et al. 2010

Cancer

108

View full text Add to dashboard Cite

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“…Using a well-established ACI rat model, Kristy R et al identified morphological and epigenetic changes in the mammary gland tissue after exposure to constitutively elevated estrogen levels, and found that progressive hyperproliferative changes were paralleled by epigenetic disturbances, which demonstrates that the hyperacetylation of histone induced by estrogen has a significant role in the early stage of breast cancer development (Kutanzi et al, 2010). Chen et al have reported that p300/CBP and PCAF mediate hyperacetylation of histone H3, H4 and transcriptional activation of ER target genes induced by estrogen in MCF-7 cells (Chen et al, 1999;Jin et al, 2010;Jin et al, 2011). PCAF predominantly acetylates histone H3.…”

Section: Discussionmentioning

confidence: 99%

Garcinol, an Acetyltransferase Inhibitor, Suppresses Proliferation of Breast Cancer Cell Line MCF-7 Promoted by 17β-Estradiol

Xia¹,

Liu²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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The acetyltransferase inhibitor garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Anti-cancer activity has been suggested but there is no report on its action via inhibiting acetylation against cell proliferation, cell cycle progression, and apoptosis-inhibtion induced by estradiol (E 2 ) in human breast cancer MCF-7 cells. The main purposes of this study were to investigate the effects of the acetyltransferase inhibitor garcinol on cell proliferation, cell cycle progression and apoptosis inhibition in human breast cancer MCF-7 cells treated with estrogen, and to explore the significance of changes in acetylation levels in this process. We used a variety of techniques such as CCK-8 analysis of cell proliferation, FCM analysis of cell cycling and apoptosis, immunofluorescence analysis of NF-κB/ p65 localization, and RT-PCR and Western blotting analysis of ac-H3, ac-H4, ac-p65, cyclin D1, Bcl-2 and Bclxl. We found that on treatment with garcinol in MCF-7 cells, E 2 -induced proliferation was inhibited, cell cycle progression was arrested at G0/G1 phase, and the cell apoptosis rate was increased. Expression of ac-H3, ac-H4 and NF-κB/ac-p65 proteins in E 2 -treated MCF-7 cells was increased, this being inhibited by garcinol but not ac-H4.The nuclear translocation of NF-κB/p65 in E 2 -treated MCF-7 cells was also inhibited, along with cyclin D1, Bcl-2 and Bcl-xl in mRNA and protein expression levels. These results suggest that the effect of E 2 on promoting proliferation and inhibiting apoptosis is linked to hyperacetylation levels of histones and nonhistone NF-κB/ p65 in MCF-7 cells. The acetyltransferase inhibitor garcinol plays an inhibitive role in MCF-7 cell proliferation promoted by E 2 . Mechanisms are probably associated with decreasing ac-p65 protein expression level in the NF-κB pathway, thus down-regulating the expression of cyclin D1, Bcl-2 and Bcl-xl.

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“…5F; r 2 ¼ 0.63 and P < 0.0001). Because it has been shown that the DNA methyltransferase-1 (DNMT1) binds to BRCA1 promoter inducing its methylation (30) and large-scale 2-hybrid assay revealed that TNRC9 interacted with DNMT1 in mice (31), we examined the role of TNRC9 in DNMT1 activity. The gene silencing of TNRC9 in ZR-75-1 breast cancer cells decreased significantly DNMT1 binding to BRCA1 promoter (Fig.…”

Section: Tnrc9 Induces Brca1 Promoter Methylationmentioning

confidence: 99%

TNRC9 Downregulates BRCA1 Expression and Promotes Breast Cancer Aggressiveness

et al. 2013

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Although the linkage between germline mutations of BRCA1 and hereditary breast/ovarian cancers is well established, recent evidence suggests that altered expression of wild-type BRCA1 might contribute to the sporadic forms of breast cancer. The breast cancer gene trinucleotide-repeat-containing 9 (TNRC9; TOX3) has been associated with disease susceptibility but its function is undetermined. Here, we report that TNRC9 is often amplified and overexpressed in breast cancer, particularly in advanced breast cancer. Gene amplification was associated with reduced disease-free and metastasis-free survival rates. Ectopic expression of TNRC9 increased breast cancer cell proliferation, migration, and survival after exposure to apoptotic stimuli. These phenotypes were associated with tumor progression in a mouse model of breast cancer. Gene expression profiling, protein analysis, and in silico assays of large datasets of breast and ovarian cancer samples suggested that TNRC9 and BRCA1 expression were inversely correlated. Notably, we found that TNRC9 bound to both the BRCA1 promoter and the cAMP-responsive element-binding protein (CREB) complex, a regulator of BRCA1 transcription. In support of this connection, expression of TNRC9 downregulated expression of BRCA1 by altering the methylation status of its promoter. Our studies unveil a function for TNRC9 in breast cancer that highlights a new paradigm in BRCA1 regulation. Cancer Res; 73(9); 2840-9. Ó2013 AACR.

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UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer

Cited by 99 publications

References 32 publications

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

Garcinol, an Acetyltransferase Inhibitor, Suppresses Proliferation of Breast Cancer Cell Line MCF-7 Promoted by 17β-Estradiol

TNRC9 Downregulates BRCA1 Expression and Promotes Breast Cancer Aggressiveness

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