EZH2 dependent H3K27me3 is involved in epigenetic silencing of ID4 in prostate cancer

Chinaranagari, Swathi; Sharma, Pankaj; Chaudhary, Jaideep

doi:10.18632/oncotarget.2262

Cited by 51 publications

(46 citation statements)

References 55 publications

(73 reference statements)

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“…These findings were in accordance with previous studies that showed an increase in the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)-mediated histone methyl transferase activity in PCa [68][69][70][71][72]. Among the perturbed metabolites, sarcosine was significantly increased during disease progression from normal through localized to metastatic PCa, and was detectable in urine.…”

supporting

confidence: 92%

Metabolomic profiling for the identification of novel diagnostic markers in prostate cancer

Lucarelli

Rutigliano

Galleggiante

et al. 2015

Expert Review of Molecular Diagnostics

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Metabolomic profiling offers a powerful methodology for understanding the perturbations of biochemical systems occurring during a disease process. During neoplastic transformation, prostate cells undergo metabolic reprogramming to satisfy the demands of growth and proliferation. An early event in prostate cell transformation is the loss of capacity to accumulate zinc. This change is associated with a higher energy efficiency and increased lipid biosynthesis for cellular proliferation, membrane formation and cell signaling. Moreover, recent studies have shown that sarcosine, an N-methyl derivative of glycine, was significantly increased during disease progression from normal to localized to metastatic prostate cancer. Mapping the metabolomic profiles to their respective biochemical pathways showed an upregulation of androgen-induced protein synthesis, an increased amino acid metabolism and a perturbation of nitrogen breakdown pathways, along with high total choline-containing compounds and phosphocholine levels. In this review, the role of emerging biomarkers is summarized, based on the current understanding of the prostate cancer metabolome.

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supporting

confidence: 92%

Metabolomic profiling for the identification of novel diagnostic markers in prostate cancer

Lucarelli

Rutigliano

Galleggiante

et al. 2015

Expert Review of Molecular Diagnostics

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“…The evidence for regulation of DNMT1 by miR-342 is further supported by studies on prostate cells, where both ID4 and DNMT1 show interactions in both cell lines and prostate cancer tissue (47) where up-or down-regulation of CEACAM1 is also observed (51). Taken together, the fine-tuning of the lumen formation program involves two negative acting signals.…”

Section: Discussionmentioning

confidence: 74%

“…Cells-The ID4 promoter has been shown to be hypermethylated in prostate cancer via recruitment of EZH2 and DNMT1 that methylate histone 3 at lysine 27, and a CpG island in the ID4 promoter, respectively (47). Although the EVL promoter is hypermethylated in many cancers, leading to the coordinated suppression of both EVL and miR-342 (27), we must conclude that the opposite situation exists in MCF7 cells because both EVL and miR-342 expression are high (Fig.…”

Section: Dnmt1 Is a Target Of Mir-342 In Mcf7mentioning

confidence: 99%

miRNA-342 Regulates CEACAM1-induced Lumen Formation in a Three-dimensional Model of Mammary Gland Morphogenesis

Weng

Shively

2016

Journal of Biological Chemistry

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Lumen formation of breast epithelium is rapidly lost during tumorigenesis along with expression of cell adhesion molecule CEACAM1. CEACAM1 induces lumena in a three-dimensional culture of MCF7/CEACAM1 cells that otherwise fail to form lumena. We hypothesized miRNAs may be involved because >400 genes were up-or down-regulated in MCF7/CEACAM1 cells and miRNAs may modify global expression patterns. Comparative analysis of miRNA expression in MCF7 versus MCF7/ CEACAM1 cells revealed two miRNAs significantly down-regulated (hsa-miR-30a-3p by 6.73-fold and hsa-miR-342-5p by 5.68-fold). Location of miR-342 within an intron of the EVL gene, hypermethylated and involved in tumorigenesis, suggested that miR-342 overexpression may block lumen formation. In fact, overexpression of miR-342 in MCF7/CEACAM1 cells significantly blocked lumen formation (p < 0.001). ID4, a dominant-negative inhibitor of basic helix-loop-helix transcription factors, up-regulated in MCF7/CEACAM1 cells, down-regulated in breast cancer, and containing a miR-342 binding site, was tested as a potential target of miR-342. The ratio of ID4 to miR-342 increased from 1:2 in MCF7 cells to 30:1 in MCF7/ CEACAM1 cells and a miR-342 inhibitor was able to induce 3-UTR ID4 reporter activity in MCF7 cells. Because 5-methylcytosine methyltransferase DNMT1 is also a potential target of miR-342, we inhibited miR-342 in MCF7 cells and found DNMT1 was up-regulated with no change in EVL expression, suggesting that miR-342 regulates DNMT1 expression but DNMT1 does not affect the EVL expression in these cells. We conclude that the regulation of lumen formation by miR-342 involves at least two of its known targets, namely ID4 and DNMT1.Lumen formation of mammary epithelial cells in a threedimensional culture is an in vitro assay that phenocopies mammary epithelial gland formation (1-3). The loss of lumen formation as exhibited by most, if not all, breast cancer cells in the three-dimensional culture assay phenocopies the premalignant stage of breast cancer know as ductal carcinoma in situ. One approach to identify genes that may govern the change from normal to (pre)malignancy is to transfect breast cancer cells with genes down-regulated in breast cancer and assay their regain of function in the lumen formation assay. A second approach is to block suspect gene expression in breast cancer cells for regain of function, or block gene expression in normal breast epithelial cells for loss of function. One gene that stands out in these assays is the cell-cell adhesion molecule CEACAM1 that is highly expressed in normal breast with a luminal expression pattern (4, 5), and is consistently down-regulated in premalignant and invasive breast cancer (4, 5).Previously, we have shown that transfection of CEACAM1 into MCF7 breast cancer cells resulted in lumen formation when the cells were cultured three-dimensionally (6), whereas anti-CEACAM1 antibodies blocked lumen formation of the normal breast epithelial cell line MCF10F that express CEACAM1 (5). Although CEACAM1 is expressed as mu...

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“…In addition, this knowledge may shed light on understanding how ID4 is down-regulated during tumorigenesis. Because ID4 gene silencing by hyper-methylation has been widely reported (13), it was likely that the same situation exists in MCF7 cells. To test this idea, parental MCF7 cells were treated with a combination of 5-aza-2Ј-deoxycytidine (DAC), a DNMT inhibitor, and trichostatin A (TSA), a histone deacetylase inhibitor to effect global chromatin re-modeling and demethylation.…”

Section: Id4 Gene Hyper-methylation and Silencing Can Be Reversed By mentioning

confidence: 97%

“…The ID4 gene that is frequently silenced by hypermethylation (13,14) is indeed hypermethylated in parental MCF7 cells, suggesting that this silencing affects lumen formation, a critical pathway in maintaining the normal differentiated state of mammary epithelial cells. The fact that introduction of CEACAM1 into MCF7 cells that have lost the ability to express CEACAM1, restores ID4 expression suggests a direct link between CEACAM1 expression and relief of the gene silencing of ID4.…”

mentioning

confidence: 99%

Induction of Lumen Formation in a Three-dimensional Model of Mammary Morphogenesis by Transcriptional Regulator ID4

Shively

2016

Journal of Biological Chemistry

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Concomitant loss of lumen formation and cell adhesion protein CEACAM1 is a hallmark feature of breast cancer. In a threedimensional culture model, transfection of CEACAM1 into MCF7 breast cells can restore lumen formation by an unknown mechanism. ID4, a transcriptional regulator lacking a DNA binding domain, is highly up-regulated in CEACAM1-transfected MCF7 cells, and when down-regulated with RNAi, abrogates lumen formation. Conversely, when MCF7 cells, which fail to form lumena in a three-dimensional culture, are transfected with ID4, lumen formation is restored, demonstrating that ID4 may substitute for CEACAM1. After showing the ID4 promoter is hypermethylated in MCF7 cells but hypomethylated in MCF/ CEACAM1 cells, ID4 expression was induced in MCF7 cells by agents affecting chromatin remodeling and methylation. Mechanistically, CaMK2D was up-regulated in CEACAM1-transfected cells, effecting phosphorylation of HDAC4 and its sequestration in the cytoplasm by the adaptor protein 14-3-3. CaMK2D also phosphorylates CEACAM1 on its cytoplasmic domain and mutation of these phosphorylation sites abrogates lumen formation. Thus, CEACAM1 is able to maintain the active transcription of ID4 by an epigenetic mechanism involving HDAC4 and CaMK2D, and the same kinase enables lumen formation by CEACAM1. Because ID4 can replace CEACAM1 in parental MCF7 cells, it must act downstream from CEACAM1 by inhibiting the activity of other transcription factors that would otherwise prevent lumen formation. This overall mechanism may be operative in other cancers, such as colon and prostate, where the down-regulation of CEACAM1 is observed.Lumen formation, a central feature of mammary morphogenesis, is lost during mammary tumorigenesis, starting with filling in the lumen with cancer cells in ductal carcinoma in situ (1) and becoming more evident in invasive solid tumors (2). Identification of the molecules that change during this process and the underlying mechanisms causing these changes are major goals of breast cancer research. Among the many molecules identified so far, CEACAM1 stands out as a luminal expressed protein that is rapidly down-regulated in both ductal carcinoma in situ (3) and invasive breast cancer (2). Not surprisingly, luminal expression of CEACAM1 occurs throughout ductal tissues such as the liver, digestive and urogenital tract, and prostate, and its loss upon malignant transformation is one of the earliest events observed (4). To study its role in lumen formation, we originally placed MCF10F, a cell line that expresses CEACAM1, in a three-dimensional culture system pioneered by Bissell and co-workers (5), and observed lumen formation with CEACAM1 at the luminal surface (3). When its expression was blocked by antisense, anti-CEACAM1 antibody, or peptides derived from the N terminus of CEACAM1, lumen formation was abrogated, demonstrating that its expression played a central role in the complex process of lumenogenesis (3). As a next step, we demonstrated that MCF7 breast cancer cells that fail to express CEACAM1 o...

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EZH2 dependent H3K27me3 is involved in epigenetic silencing of ID4 in prostate cancer

Cited by 51 publications

References 55 publications

Metabolomic profiling for the identification of novel diagnostic markers in prostate cancer

Metabolomic profiling for the identification of novel diagnostic markers in prostate cancer

miRNA-342 Regulates CEACAM1-induced Lumen Formation in a Three-dimensional Model of Mammary Gland Morphogenesis

Induction of Lumen Formation in a Three-dimensional Model of Mammary Morphogenesis by Transcriptional Regulator ID4

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