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Evi1 forms a bridge between the epigenetic machinery and signaling pathways.

ABSTRACT: Recent studies have demonstrated the significance of the leukemia oncogene Evi1 as the regulator of hematopoietic stem cells and marker of poor clinical outcomes in myeloid malignancies. Evi1-mediated leukemogenic activities include a wide array of functions such as the induction of epigenetic modifications, transcriptional control, and regulation of signaling pathways. We have recently succeeded in comprehensively elucidating the oncogenic function of Evi1 in a model of the polycomb-Evi1-PTEN/AKT/mTOR axis. These results may provide us with novel therapeutic approaches to conquer the poor prognosis associated with Evi1-activated leukemia or other solid tumors with high Evi1 expression. Here, we review the current understanding of the role of Evi1 in controlling the development of leukemia and highlight potential modalities for targeting factors involved in Evi1-regulated signaling.

SUBMITTER: Yoshimi A

PROVIDER: S-EPMC3248179 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Evi1 forms a bridge between the epigenetic machinery and signaling pathways.

Yoshimi Akihide A Kurokawa Mineo M

Oncotarget 20110701 7

Recent studies have demonstrated the significance of the leukemia oncogene Evi1 as the regulator of hematopoietic stem cells and marker of poor clinical outcomes in myeloid malignancies. Evi1-mediated leukemogenic activities include a wide array of functions such as the induction of epigenetic modifications, transcriptional control, and regulation of signaling pathways. We have recently succeeded in comprehensively elucidating the oncogenic function of Evi1 in a model of the polycomb-Evi1-PTEN/A ...[more]

PMID: 21795762

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Project description:BackgroundThe epithelial-mesenchymal transition (EMT) is a de-differentiation process required for wound healing and development. In tumors of epithelial origin aberrant induction of EMT contributes to cancer progression and metastasis. Studies have begun to implicate epigenetic reprogramming in EMT; however, the relationship between reprogramming and the coordination of cellular processes is largely unexplored. We have previously developed a system to study EMT in a canonical non-small cell lung cancer (NSCLC) model. In this system we have shown that the induction of EMT results in constitutive NF-κB activity. We hypothesized a role for chromatin remodeling in the sustained deregulation of cellular signaling pathways.ResultsWe mapped sixteen histone modifications and two variants for epithelial and mesenchymal states. Combinatorial patterns of epigenetic changes were quantified at gene and enhancer loci. We found a distinct chromatin signature among genes in well-established EMT pathways. Strikingly, these genes are only a small minority of those that are differentially expressed. At putative enhancers of genes with the 'EMT-signature' we observed highly coordinated epigenetic activation or repression. Furthermore, enhancers that are activated are bound by a set of transcription factors that is distinct from those that bind repressed enhancers. Upregulated genes with the 'EMT-signature' are upstream regulators of NF-κB, but are also bound by NF-κB at their promoters and enhancers. These results suggest a chromatin-mediated positive feedback as a likely mechanism for sustained NF-κB activation.ConclusionsThere is highly specific epigenetic regulation at genes and enhancers across several pathways critical to EMT. The sites of these changes in chromatin state implicate several inducible transcription factors with critical roles in EMT (NF-κB, AP-1 and MYC) as targets of this reprogramming. Furthermore, we find evidence that suggests that these transcription factors are in chromatin-mediated transcriptional feedback loops that regulate critical EMT genes. In sum, we establish an important link between chromatin remodeling and shifts in cellular reprogramming.

Project description:The loss of anti-proliferative responsiveness in prostate cancer cell lines toward ligands for vitamin D receptor, retinoic acid receptors/retinoid X receptors and peroxisome proliferator activated receptor (PPAR)alpha/gamma may entail underlying epigenetic events, as ligand insensitivity reflects significantly altered messenger RNA expression of corepressors and histone-modifying enzymes. Expression patterns were dependent on phases of the cell cycle and associated with repressed basal gene expression of vitamin D receptor and PPARalpha/gamma target genes, for example CDKN1A [encodes p21((waf1/cip1))]. Elevated nuclear corepressor 1 (NCOR1) and nuclear corepressor 2/silencing mediator of retinoic acid and thyroid hormone receptor protein levels were detected in prostate cancer cell lines compared with non-malignant counterparts. Knockdown of the corepressor NCOR1 significantly elevated basal expression of a cohort of target genes, including CDKN1A. Both chemical [histone deacetylases inhibitor (HDACi)] and NCOR1 knockdown targeting enhanced anti-proliferative sensitivity toward PPARalpha/gamma ligands in prostate cancer cell lines. Pursuing PPARalpha/gamma signaling, microarray approaches were undertaken to identify pathways and genes regulated uniquely by a combination of PPARalpha/gamma activation and HDAC inhibition. Again, HDACi and knockdown approaches demonstrated that elevated NCOR1 expression and activity distorted PPARalpha/gamma gene targets centered on, for example cell cycle control, including CDKN1A and TGFBRAP1. Quantitative real time polymerase chain reaction validation and chromatin immunoprecipitation assays both confirmed that elevated NCOR1 disrupted the ability of PPARalpha/gamma to regulate key target genes (CDKN1A and TGFBRAP1). Interrogation of these relationships in prostate cancer samples using principal component and partial correlation analyses established significant interdependent relationships between NCOR1-PPARalpha/gamma and representative target genes, independently of androgen receptor expression. Therefore, we conclude that elevated NCOR1 distorts the actions of PPARalpha/gamma selectively and generates a potential epigenetic lesion with diagnostic and prognostic significance.

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Evi1 forms a bridge between the epigenetic machinery and signaling pathways.

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Evi1 forms a bridge between the epigenetic machinery and signaling pathways.

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