Interplay between Menin and K-Ras in Regulating Lung Adenocarcinoma

Wu, Yuan; Feng, Zijie; Gao, Shu-Bin; Matkar, Smita; Xu, Bin; Duan, Hongbin; Lin, Xiao; Li, Shan-Hua; Hua, Xianxin; Jin, Guang‐Hui

doi:10.1074/jbc.m112.382416

Cited by 39 publications

(37 citation statements)

References 42 publications

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“…These findings suggest a potential feedback loop of tumor suppressor P53 and tumor promoter gene EZH2, an important interplay governing tumor activation and suppression in the development of HCC. This process is similar to our previous reports that the interplay between oncogene K-Ras and tumor suppressor menin plays an important role in regulating the development of lung cancer (17). However, it is unclear whether the activated P53 suppresses the expression of EZH2 in HCC.…”

Section: Discussionsupporting

confidence: 75%

“…Wilm's (human nephroblastoma), MCF-7 (human mammary gland adenocarcinoma), and A549 (human lung adenocarcinoma) were obtained from the Cell Culture Center of the School of Basic Medicine, Peking Union Medical College (Beijing, China). The cell cultures were performed as previously described (16)(17)(18)(19). Briefly, the cells were cultured in DMEM (Gibco), RPMI-1640 medium (Gibco), or F12 (Gibco) supplemented with 10% FBS (Hyclone) and 1% penicillin-streptomycin.…”

Section: Cell Culturementioning

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: Discussionsupporting

confidence: 75%

Section: Cell Culturementioning

confidence: 99%

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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“…To explore how menin influences liver cancer cells, the HepG2 cells were stably transfected with either a control (shLuc) or shMEN1 (17). MEN1 shRNA substantially repressed HepG2 cell proliferation and colony forming activity (CFA) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Zheng

et al. 2013

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

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Significance Epigenetic changes commonly occur in hepatocellular carcinoma (HCC) and are associated with aberrant gene expression. Most studies have focused on epigenetic gene-silencing events; therefore, the mechanism that promotes gene activation in HCC is not well established. We identify an epigenetic activation mechanism whereby menin promotes Yes-associated protein (Yap1) transcription, which is associated with a poor prognosis for HCC patients. Substantial overexpression of the menin–mixed-lineage leukemia complex is associated with increased histone 3 lysine 4 trimethylation at certain loci of the tumor promoter in HCC. Heterozygous ablation of multiple endocrine neoplasia type 1 ( Men1) in mice reduces diethylnitrosamine-induced development of HCC. Our findings reveal that menin plays an important epigenetic role in up-regulating Yap1 transcription, leading to liver tumorigenesis.

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“…ND, none detected. 4 0 9 9 jci.org Volume 124 Number 9 September 2014 transcriptional regulators and cell signaling pathway components through direct protein-protein interactions (52)(53)(54). Identifying the unique targets of the MAPK pathway in menin WT and mutant endocrine cells may provide insight into the unique sensitivity of endocrine cells to loss of menin.…”

Section: Discussionmentioning

confidence: 99%

Menin determines K-RAS proliferative outputs in endocrine cells

et al. 2014

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R e s e a R c h a R t i c l e4 0 9 4 jci.org Volume 124 Number 9 September 2014 het; Figure 1B). We discovered that pancreata from E13.5 Kras-het embryos contained more endocrine cells, as determined by combined glucagon and insulin staining, than did WT pancreata, while overall pancreatic size remained unchanged (Figure 1, C-E, and Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI69004DS1). By P5, Kras-het animals had a relative expansion of both the glucagon-expressing α cell and insulin-expressing β cell populations without any increase in the exocrine pancreas (Figure 1, F-H, and Supplemental Figure 2). Further, Kras-het adults had improved glucose tolerance compared with that of WT controls (Supplemental Figure 3), consistent with an increase in functional β cell capacity. Next, we sought to determine the source of additional endocrine cells in Kras-het animals. The fetal pancreas generates endocrine cells by neogenesis, followed by rapid expansion of those cells by proliferation during perinatal and postnatal growth (Figure 2A and ref. 13). Using expression of the transcription factor NEUROG3 to identify the transient precursor cells generated susceptible to MEN1 gene mutation, menin normally prevents the MAPK effector pathway from driving proliferation, while leaving inhibitory effector pathways such as RASSF1A intact. In this model, loss of menin causes proliferation in susceptible cells due to removal of the blockage of MAPK-driven proliferation downstream of K-RAS, while loss of K-RAS signaling increases proliferation by decreasing unopposed RASSF1A activity. Our data explain the absence of activating KRAS mutations and the high frequency of MEN1 and RASSF1A inactivation in pancreatic endocrine tumors. Our study also suggests potential antiproliferative strategies for treating these tumors and proproliferative therapies for diseases that result from a deficiency of endocrine cell types, such as β cells, in both type 1 and type 2 diabetes. ResultsTo test K-RAS function in pancreatic endocrine cell growth, we used mice carrying the Kras G12D allele, which is a null allele in the absence of Cre recombinase (12), in place of 1 WT allele (Kras- G12D-knock-in allele, which contains the G12D mutation in exon 2 and an upstream LoxP-Stop-LoxP sequence (12), to an active allele expressing constitutively active K-RAS G12D after Cre-mediated recombination. (C and D) Projection images of the dorsal pancreas were collected by whole-mount confocal microscopy from E13.5 mouse embryos of the indicated genotypes and immunostained for E-cadherin (blue) and glucagon and insulin (green) (n = 6 Kras WT, n = 6 Kras-het). (E) Quantification of immunostained areas in the epithelial pancreas (E-cadherin) and endocrine pancreas (glucagon and insulin) relative to WT embryos. (F-H) Pancreatic sections from P5 WT (F) and Kras-het (G) neonates were immunostained for glucagon (red) and insulin (green), with quantification of the relative insulin and glucagon areas and pancreatic mass (H...

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Interplay between Menin and K-Ras in Regulating Lung Adenocarcinoma

Cited by 39 publications

References 42 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

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Menin determines K-RAS proliferative outputs in endocrine cells

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