2015
DOI: 10.1016/j.celrep.2015.06.078
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Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape

Abstract: Summary Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRasG12V or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, while both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor ne… Show more

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Cited by 38 publications
(31 citation statements)
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“…Endocrine responses in estrogen receptor (ER) positive breast cancer are dependent on the transcription factor FOXA1, as it regulates ER/enhancer interactions and transcriptional activity (26). In the context of oncogenic kinase signaling, perturbation of ERK signaling by Sprouty deletion or G12V HRas expression remodel histone modifications at both super-enhancers and classical enhancers by distinct mechanisms (27). Looping of the MET enhancer leading to the binding of the transcriptional start site in a 3C assay was shown to be regulated in response to BRaf inhibition (28).…”
Section: Discussionmentioning
confidence: 99%
“…Endocrine responses in estrogen receptor (ER) positive breast cancer are dependent on the transcription factor FOXA1, as it regulates ER/enhancer interactions and transcriptional activity (26). In the context of oncogenic kinase signaling, perturbation of ERK signaling by Sprouty deletion or G12V HRas expression remodel histone modifications at both super-enhancers and classical enhancers by distinct mechanisms (27). Looping of the MET enhancer leading to the binding of the transcriptional start site in a 3C assay was shown to be regulated in response to BRaf inhibition (28).…”
Section: Discussionmentioning
confidence: 99%
“…Thus, it is tempting to speculate that the reduction of H3Ac upon Nipped-A knockdown contributes to the observed loss of ISC identity and proliferation. A recent report found an increase in H3K27Ac at enhancers of genes that were important for oncogenesis after induction of HRas G12V in mouse embryonic fibroblasts (MEFs) (Nabet et al, 2015). Also, H3K27Ac has been shown to be upregulated in colon cancer (Karczmarski et al, 2014).…”
Section: Discussionmentioning
confidence: 99%
“…In addition, we tested the acetylation status of H3K27 (Fig. S7), an active histone mark that has been associated with increased proliferation in colon cancer and deregulated Ras signaling (Karczmarski et al, 2014;Nabet et al, 2015). Strikingly, knocking down Nipped-A led to a dramatic decrease in H3K27Ac after 14 and 28 days (Fig.…”
Section: Nipped-a Modulates Global Acetylation Of H3 and H4mentioning
confidence: 99%
“…Additional, epigenomic mechanisms also lead to SE formation in cancer, such as those associated with oncogenic TF overexpression (Hnisz et al, 2013), the global function of oncogenic TF fusions (e.g. EWS-FLI) (Kennedy et al, 2015; Tomazou et al, 2015), and the consequences of upstream oncogenic signaling (e.g., RAS-dependent signaling to chromatin) (Nabet et al, 2015). …”
Section: Transcriptional Dysregulation In Cancermentioning
confidence: 99%