Dataset Information

C-Myc is Required for BRAFV600E-Induced Epigenetic Silencing by H3K27me3 in Tumorigenesis.

ABSTRACT: BRAFV600E mutation is frequently found in human cancers particularly thyroid cancer and melanoma, and is involved in the regulation of gene expression through activating MAPK/Erk signaling. Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing in tumorigenesis. However, molecular mechanism underlying the complex interplay between these two molecular events remains to be explored. In the present study, we conducted chromatin immunoprecipitation combined with next-generation sequencing (ChIP-Seq) and expression microarray analysis in NIH3T3 cells to explore the relationship between H3K27me3 and transcriptional regulation by BRAFV600E mutation. Our results showed that activated MAPK/Erk signaling by BRAFV600E mutation was a trigger of this epigenetic processing at many downstream target genes in cancer cell lines and BrafV600E-induced thyroid cancer of transgenetic mice. By integrating ChIP-Seq and gene expression microarray data, we identified 150 down-regulated loci with increased levels of H3K27me3 in BRAF-mutant cells relative to BRAF wild-type cells. Our data also demonstrated that c-Myc, a downstream key effector of BRAFV600E signaling, was required for BRAFV600E-induced changes in H3K27me3 through regulating the components of the polycomb repressive complex 2 (PRC2) genes Ezh2, Suz12 and Jarid2 at both transcriptional levels via direct binding to their regulatory elements and post-transcriptional levels via repressing the miR-26a, miR-200b and miR-155. In addition, BRAFV600E also caused gene silencing through Erk1/2-induced RNA polymerase II (RNAPII) poising and chromatin architecture. Collectively, our data uncover a previously unknown epigenetic mechanism in the tumorigenesis of BRAFV600E-driven cancers.

SUBMITTER: Qu Y

PROVIDER: S-EPMC5485424 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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c-Myc is Required for BRAFV600E-Induced Epigenetic Silencing by H3K27me3 in Tumorigenesis.

Qu Yiping Y Yang Qi Q Liu Juan J Shi Bingyin B Ji Meiju M Li Gang G Hou Peng P

Theranostics 20170526 7

BRAFV600E mutation is frequently found in human cancers particularly thyroid cancer and melanoma, and is involved in the regulation of gene expression through activating MAPK/Erk signaling. Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing in tumorigenesis. However, molecular mechanism underlying the complex interplay between these two molecular events remains to be explored. In the present study, we conducted c ...[more]

PMID: 28656062

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Project description:BACKGROUND: Basal-like breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Recent studies have linked activation of the Wnt/?-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5?N?cat previously generated by our team present a constitutive activation of Wnt/?-catenin signaling in the basal myoepithelial cell layer, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5?N?cat mice consist essentially of basal epithelial cells that, in contrast to mammary myoepithelium, do not express smooth muscle markers. METHODS: Microarray analysis was used to compare K5?N?cat mouse tumors to human breast tumors, mammary cancer cell lines and the tumors developed in other mouse models. Cre-Lox approach was employed to delete Myc from the mammary basal cell layer of K5?N?cat mice. Stem cell amplification in K5?N?cat mouse mammary epithelium was assessed with 3D-culture and transplantation assays. RESULTS: Histological and microarray analyses of the mammary lesions of K5?N?cat females revealed their high similarity to a subset of basal-like human breast tumors with squamous differentiation. As in human basal-like carcinomas, the Myc pathway appeared to be activated in the mammary lesions of K5?N?cat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5?N?cat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5?N?cat mice not only abolished the regenerative capacity of basal epithelial cells, but, in addition, completely prevented the tumorigenesis. CONCLUSIONS: These results strongly indicate that ?-catenin-induced stem cell amplification and tumorigenesis rely ultimately on the Myc pathway activation and reinforce the hypothesis that basal stem/progenitor cells may be at the origin of a subset of basal-like breast tumors.

Dataset Information

C-Myc is Required for BRAFV600E-Induced Epigenetic Silencing by H3K27me3 in Tumorigenesis.

Publications

c-Myc is Required for BRAF<sup>V600E</sup>-Induced Epigenetic Silencing by H3K27me3 in Tumorigenesis.

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