Two distinct mechanisms of silencing by the KvDMR1 imprinting control region

Shin, Jong-Yeon; Fitzpatrick, Galina V.; Higgins, Michael J.

doi:10.1038/sj.emboj.7601960

Cited by 123 publications

(128 citation statements)

References 45 publications

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“…In our published report, we showed that PREX2 mutation or PTEN deletion induces DNA hypomethylation at the critical imprint control region of p57 and IGF2 which has the well-known effect of downregulating p57 and upregulating IGF2. [15][16][17] Here, we provide further information that support these observations. First, we performed global chromatin immunoprecipitation and sequencing (ChIP-Seq) analysis of an additional epigenetic regulatory mark which is implicated in regulation of genomic imprinting, i.e Histone H4 lysine 20 methylation.…”

supporting

confidence: 73%

“…First, we performed global chromatin immunoprecipitation and sequencing (ChIP-Seq) analysis of an additional epigenetic regulatory mark which is implicated in regulation of genomic imprinting, i.e Histone H4 lysine 20 methylation. 16,18,19 We investigated all 3 possible methylation marks, (H4K20) mono-(Me1), di-(Me2) and tri-methylation (Me3), in primary immortalized melanocytes. We observed significant global reduction in H4K20Me3, but not in H4K20Me1 and Me2, in cells expressing PREX2 mutants as compared to GFP control and wildtype PREX2 ( Fig.…”

mentioning

confidence: 99%

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Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma

Deribe

2016

Small GTPases

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PREX2 is a PTEN interacting protein that is significantly mutated in melanoma and pancreatic ductal adenocarcinoma. Recently, we reported the mechanistic basis of melanomagenesis by PREX2 mutations. Truncating PREX2 mutations activate its guanine nucleotide exchange factor activity for its substrate RAC1. This leads to increased PI3K/AKT signaling associated with reduced DNA methylation and increased cell proliferation in NRAS-mutant melanoma. Here, we provide additional data that indicates a reciprocal regulation of PREX2 by PTEN whereby loss of PTEN results in a dramatic increase in expression of PREX2 at the protein level. Pharmacologic studies revealed destabilization of PREX2 by inhibition of PI3K/AKT signaling. Additionally, we provide data to show a selective decrease in a particular histone mark, H4 Lys20 trimethylation, in cells expressing PREX2 E824 Ã truncating mutation globally and at the imprint control region of CDKN1C (also known as p57) and IGF2. The decrease in H4K20 trimethylation coupled with DNA hypomethylation at this particular locus is associated with genomic imprinting and regulation of expression of p57 and IGF2. Taken together, these results demonstrate the complex signaling mechanisms that involve PREX2, PI3K/AKT/PTEN and downstream epigenetic machinery to deregulate expression of key cell cycle regulators. Recent next generation DNA sequencing of tumors have provided insight into the complexity of somatic mutations and given us a compendium of novel significantly mutated cancer genes.1 It is expected that functional genomic studies will provide detailed molecular and functional roles for these mutations in tumor development. We identified PREX2 (phosphatidylinositol-3, 4, 5-triphosphatedependent Rac-exchange factor 2) as being significantly mutated in human melanomas.2 Interestingly, the International Cancer Genomics Consortium (ICGC) recently reported that PREX2 is also significantly mutated in pancreatic ductal adenocarcinoma. 3PREX2 is a guanine nucleotide exchange factor (GEF) for RAC1 and is a known PTEN binding protein. 4,5 Mechanistically, PREX2 has been shown to regulate RAC1 mediated cellular invasion in a manner that cross-talks with PTEN signaling and also regulates insulin signaling and glucose homeostasis through the PI3K pathway.6,7 Initial melanoma genome sequencing studies showed various patterns of PREX2 mutations including missense and truncating mutations. Using xenograft models, we were able to show that truncating PREX2 mutations have oncogenic activity. However, the exact mechanism behind PREX2 mutations driven melanoma development was unclear.To study PREX2 mutations in a tissue and time restricted manner, we generated an inducible transgenic mouse model that expresses a truncating PREX2 mutant (TetO-lox-STOP-lox-PREX2 E824 Ã ) in melanocytes. 8 We crossed these transgenic mice with mice that have a melanoma sensitizing background, i.e. lack the tumor suppressor Ink/Arf and inducibly express a constitutively active NRAS Q61K to generate a genetically eng...

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supporting

confidence: 73%

mentioning

confidence: 99%

Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma

Deribe

2016

Small GTPases

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“…The promoter for the Kcnq1ot1 gene resides within KvDMR1 [14]. According [38], Kcnq1ot1 is required for epigenetic silencing of neighboring genes upstream and downstream of the Kcnq1 locus.…”

Section: Imprinted Genes: Regulation and Functionmentioning

confidence: 99%

Loss of Imprinting as an Epigenetic Marker in Bladder Cancer

Reis¹,

Rainho²

2013

Advances in the Scientific Evaluation of Bladder Cancer and Molecular Basis for Diagnosis and Treatment

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“…However, the mechanism(s) regulating methylation at the DMR has not been elucidated. Hence, we first asked whether down-regulation of CDKN1C in PREX2 mutant cells is associated with changes in the methylation status of the DMR (43,44). Accordingly, DNA methylation of the DMR as assessed by methylated DNA immunoprecipitation and qPCR confirmed a marked DNA hypomethylation at the imprint control region of CDKN1C in PREX2 mutant cells (Fig.…”

Section: Prex2 Mutant Tumors Have Markedly Increased Cell Proliferationmentioning

confidence: 99%

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

Deribe

Shi

Rai

et al. 2016

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

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PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2E824*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57KIP2). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.

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Two distinct mechanisms of silencing by the KvDMR1 imprinting control region

Cited by 123 publications

References 45 publications

Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma

Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma

Loss of Imprinting as an Epigenetic Marker in Bladder Cancer

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

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