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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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COLO829 treatment with PLX4032 and/or MITF knockdown

ABSTRACT: Thousands of enhancers are characterized in the human genome, yet few have been shown important in cancer. Inhibiting oncokinases, such as EGFR, ALK, HER2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by upregulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific MET enhancers for multiple common tumor types, including a melanoma lineage-specific MET enhancer that displays inducible chromatin looping and MET gene induction upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro- and anti-oncogenic functions of tumor lineage-enriched transcription factors mediating innate resistance to oncokinase therapy. COLO829 human melanoma cell line harboring the BRAFV600E mutation was treated with BRAF inhibtior PLX4032 (Vemurafenib) and/or a hairpin against MITF

ORGANISM(S): Homo sapiens

SUBMITTER: Paul Khavari

PROVIDER: E-GEOD-50649 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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MITF ChIP-seq in primary melanocyte and melanoma as a function of oncogenic BRAF

Project description:Thousands of enhancers are characterized in the human genome, yet few have been shown important in cancer. Inhibiting oncokinases, such as EGFR, ALK, HER2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by upregulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific MET enhancers for multiple common tumor types, including a melanoma lineage-specific MET enhancer that displays inducible chromatin looping and MET gene induction upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro- and anti-oncogenic functions of tumor lineage-enriched transcription factors mediating innate resistance to oncokinase therapy. MITF ChIP-seq was performed in primary human melanocytes with overexpression of BRAFV600E or a lentiviral control (RFP), and in COLO829 melanoma cells treated with DMSO, or PLX4032

2014-01-14 | E-GEOD-50681 | biostudies-arrayexpress

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COLO829 treatment with PLX4032 and/or MITF knockdown

2014-01-14 | GSE50649 | GEO

BRAF/MAPK and GSK3 signaling converges to control MITF nuclear export

Project description:The close integration of the MAPK, PI3K, and WNT signaling pathways underpins much of development and is deregulatedin cancer. In principle, combinatorial posttranslational modification of key lineage specific transcription factors would be an effective mean stointegrate critical signaling events. Understanding how this might be achieved is central to deciphering the impact of microenvironmental cues in development and disease. The microphthalmia-associated transcription factor MITF plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts, and mast cells and acts as a lineage survival oncogene in melanoma. MITF coordinates survival, differentiation, cell-cycle progression, cell migration, metabolism, and lysosome biogenesis. However, how the activity of this key transcriptionfactoriscontrolledremainspoorlyunderstood.Here,we showthatGSK3,downstreamfromboththePI3KandWntpathways, and BRAF/MAPK signaling converge to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3, a kinase inhibited by both PI3K and Wnt signaling. Dual phosphorylation, but not monophosphorylation, then promotes MITF nuclear export by activatinga previously unrecognizedhydrophobic exportsignal. NonmelanocyteMITFisoformsexhibitpoorregulationbyMAPKsignaling, but instead their export is controlled by mTOR. We uncover here an unanticipated mode of MITF regulation that integrates the output of key developmental and cancer-associated signaling pathways to gate MITF flux through the import–export cycle. The results have significant implications for our understanding of melanoma progression and stem cell renewal.

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2022-02-28 | PXD010665 | Pride

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2016-01-13 | PXD002565 | Pride

Targeting the lineage-specific long non-coding RNA LINC01212 as an effective anti-melanoma therapeutic strategy [2]

Project description:Focal amplifications of 3p13-3p14 occur in about 10% of melanoma and are associated with poor prognosis. The melanoma-specific oncogene MITF resides at the epicenter of this amplicon1. However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-coding RNA gene LINC01212 is consistently co-gained with MITF. In addition to being amplified, LINC01212 is a target of the lineage-specific transcription factor SOX10 and, consequently, it is expressed in more than 90% of human melanomas, but not in normal adult tissues. Whereas exogenous LINC01212 functions in trans to increase melanoma clonogenic potential LINC01212 knock-down dramatically decreases the viability of melanoma cells irrespective of their transcriptional cell state, BRAF, NRAS or TP53 status, diminishes melanoma growth and increases their sensitivity to MAPK-targeting therapeutics both in vitro and in patient-derived melanoma xenograft mouse models. Mechanistically, LINC01212 functions as a lineage addiction oncogene by interacting with and modulating the cellular localization and function of two proteins, XRN2 and p32, involved in nucleolar and mitochondrial rRNA processing, ribosome biogenesis and protein synthesis. LINC01212 targeting, especially in combination with BRAFV600E-inhibitors, is expected to deliver highly effective and tissue-restricted antimelanoma therapeutic responses. Five GapmeR3 treated and four control treated patient derived xenografts were analysed.

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