The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma

Gao, Shu-Bin; Xu, Bin; Ding, Lin‐Fen; Zheng, Qunhao; Zhang, Li; Zheng, Qi-Fan; Li, Shan-Hua; Feng, Zijie; Jie, Wei; Yin, Zhenyu; Hua, Xianxin; Jin, Guang‐Hui

doi:10.1016/j.jhep.2014.05.015

Cited by 50 publications

(44 citation statements)

References 27 publications

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“…A previous report found a CCCTCbinding factor (CTCF) that binds at the P53 promoter and protects the P53 gene promoter against repressive histone marks (30). Interesting findings have shown that EZH2 and SUZ12 were directly bound at CTCF promoter loci with H3K27me3 modification and that the increased accumulation of H3K27me3 at the CTCF promoter is associated with the reduction of CTCF in HCC specimens (21). These results suggest that PcG regulates P53 expression in HCC at least partly through CTCF in HCC.…”

Section: Discussionmentioning

confidence: 96%

“…Although EZH2 and SUZ12 occupy the promoter regions of thousands of human genes, only 340 genes share H3K27me3 in HepG2 (21). This result suggests that PcG regulates gene expression in both an H3K27me3-dependent and an H3K27me3-independent manner.…”

Section: Discussionmentioning

confidence: 99%

“…of PcG, which contains well-established genes, such as CDKN2A, and other previously unstudied genes in liver cancer cells, including E2F1 and NOTCH2 (21). The functional importance of these genes in controlling liver function has been established (22,23).…”

Section: Pcg Directly Controls Target Gene Transcription Through H3k2mentioning

confidence: 99%

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EZH2 Represses Target Genes through H3K27-Dependent and H3K27-Independent Mechanisms in Hepatocellular Carcinoma

Gao

Zheng

et al. 2014

Molecular Cancer Research

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Alterations of polycomb group (PcG) genes directly modulate the trimethylation of histone H3 lysine 27 (H3K27me3) and may thus affect the epigenome of hepatocellular carcinoma (HCC), which is crucial for controlling the HCC cell phenotype. However, the extent of downstream regulation by PcGs in HCC is not well defined. Using cDNA microarray analysis, we found that the target gene network of PcGs contains well-established genes, such as cyclin-dependent kinase inhibitors (CDKN2A), and genes that were previously undescribed for their regulation by PcG, including E2F1, NOTCH2, and TP53. Using chromatin immunoprecipitation assays, we demonstrated that EZH2 occupancy coincides with H3K27me3 at E2F1 and NOTCH2 promoters. Interestingly, PcG repress the expression of the typical tumor suppressor TP53 in human HCC cells, and an increased level of PcG was correlated with the downregulation of TP53 in certain HCC specimens. Unexpectedly, we did not find obvious H3K27me3 modification or an EZH2 binding signal at the TP53 promoters, suggesting that PcG regulates TP53 expression in an H3K27me3-independent manner. Finally, the reduced expression of PcGs effectively blocked the aggressive signature of liver cancer cells in vitro and in vivo.Implications: Taken together, our results establish the functional and mechanistic significance of certain gene regulatory networks that are regulated by PcGs in HCC.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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EZH2 Represses Target Genes through H3K27-Dependent and H3K27-Independent Mechanisms in Hepatocellular Carcinoma

Gao

Zheng

et al. 2014

Molecular Cancer Research

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“…5,10 By contrast, increased menin levels promote hepatocellular carcinogenesis correlating negatively with the overall and tumor-free survival rates. 6 In our case, two of the three male carriers of the Men1 mutation developed prostate cancer early. Sequencing of prostate tumor cells from patient 3 excluded LOH, which could explain these early manifestations.…”

Section: In Vivomentioning

confidence: 50%

“…lipomas, angiofibromas). 1,2 However, different atypical tumor entities have occasionally been described in families with MEN1 syndrome, [3][4][5][6] raising the following questions. Does menin have a major role in carcinogenesis, including a non-endocrine function?…”

Section: Discussionmentioning

confidence: 99%

Multiple endocrine neoplasia type 1 associated with a new germline Men1 mutation in a family with atypical tumor phenotype

Perakakis

Flohr

Kayser

et al. 2015

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FoxO3 inactivation promotes human cholangiocarcinoma tumorigenesis and chemoresistance through Keap1‐Nrf2 signaling

et al. 2016

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FoxO transcription factors have been reported to play pivotal roles in tumorigenesis and drug resistance. The mechanisms underlying the tumor suppression function of FoxOs in human cancers remain largely unknown. Aberrant expression and activation of Nrf2 often correlate with chemoresistance and poor prognosis. Here, we report that FoxO3 directs the basal transcription of Kelch-like ECH-associated protein 1 (Keap1), an adaptor protein that bridges Nrf2 to Cul3 for degradation. FoxO3 depletion resulted in Keap1 downregulation, thereby activating Nrf2 signaling. We further demonstrated that inhibition of the FoxO3-Keap1 axis accounts for Nrf2 induction and activation induced by constitutively active AKT signaling or tumor necrosis factor a treatment. Unlike previous findings, FoxO3 silencing led to decreased reactive oxygen species production, therefore protecting cells from oxidative stress-induced killing in an Nrf2-dependent manner. Importantly, FoxO3 deficiency strongly potentiated tumor formation in nude mice and rendered cholangiocarcinoma xenografts resistant to cisplatin-induced cell death by activating Nrf2. Additionally, we found that clinical cholangiocarcinoma samples displayed FoxO3-Keap1 down-regulation and Nrf2 hyperactivation, underscoring the essential roles of these proteins in cholangiocarcinoma development. Conclusion: Our results unravel a unique mechanism underlying the tumor suppressor function of

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The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma

Cited by 50 publications

References 27 publications

EZH2 Represses Target Genes through H3K27-Dependent and H3K27-Independent Mechanisms in Hepatocellular Carcinoma

EZH2 Represses Target Genes through H3K27-Dependent and H3K27-Independent Mechanisms in Hepatocellular Carcinoma

Multiple endocrine neoplasia type 1 associated with a new germline Men1 mutation in a family with atypical tumor phenotype

FoxO3 inactivation promotes human cholangiocarcinoma tumorigenesis and chemoresistance through Keap1‐Nrf2 signaling

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