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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Pieter mestdagh

PROVIDER: E-GEOD-70177 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

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 cogained 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 drastically decreases the viability of melanoma cells irrespective of their transcriptional cell state, BRAF, NRAS or TP53 status and increases their sensitivity to MAPK-targeting therapeutics both in vitro and in Patient-Derived Xenograft (PDX) models. Mechanistically, LINC01212 interacts with p32, a master regulator of mitochondrial homeostasis and metabolism, to increase its mitochondrial targeting and pro-oncogenic function. Our results indicate that targeting the lineage addiction oncogene LINC01212, especially in combination with BRAFV600Einhibitors, disrupts vital mitochondrial functions in a cancer-cell specific manner and is therefore expected to deliver highly effective and tissuerestricted anti-melanoma therapeutic responses.

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.

2016-01-15 | GSE70177 | GEO

Targeting the lineage-specific long non-coding RNA LINC01212 as an effective anti-melanoma therapeutic strategy [1]

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.

2016-01-15 | GSE70176 | GEO

Regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

Project description:The ability of cancer cells to switch phenotype in response to a dynamic intra-tumor microenvironment is a major barrier to effective therapy. In melanoma, down-regulation of the lineage addiction oncogene MITF (Microphthalmia-associated transcription factor) is a hallmark of the proliferative-to-invasive phenotype switch. Yet how MITF promotes proliferation and suppresses invasion is poorly understood. Here we show that expression of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) is activated by MITF, but suppressed by the stress-responsive transcription factor ATF4. SCD expression is required for MITF-positive melanoma cell proliferation,. By contrast, MITF-low cells express reduced levels of SCD and are insensitive to its inhibition, indicating that cell phenotype dictates response to drugs targeting lipid metabolism. Since SCD suppresses inflammatory signalling and ATF4 expression, the results identify a positive feedback-loop that can maintain an invasive phenotype, uncover a key role for MITF and ATF4 in metabolic reprograming, and reveal fatty acid composition as a driver of melanoma phenotype-switching.

2019-11-19 | PXD010254 | Pride

Modulation of the transcriptional response to TNF-alpha in the human melanoma cell line MZ7 by MITF

Project description:We analyzed the transcriptional response of the human melanoma cell line MZ7 to TNF-alpha (24 hours) in a dose-dependent manner (TNF-alpha 10U/ml, 100U/ml, 1000U/ml) either transfected with control siRNA (siNT = non-targeting siRNA) or transfected with siRNAs (pool of 4 active and independent siRNAs) against the melanocytic transcription factor and lineage oncogene MITF. (Microphthalmia-associated transcription factor). The experiment was performed as biological duplicate. As MITF is critical for melanoma cell state control, we aimed to explore how MITF expression intersects with inflammation-induced plasticity pathways in melanoma. Total RNA was obtained from siRNA/TNF-treated MZ7 melanoma cell lines at various conditions and global gene expression profiling was done using the Illumina Human HT12 v4 platform.

2015-10-29 | E-GEOD-71798 | biostudies-arrayexpress

Modulation of the transcriptional response to TNF-alpha in the human melanoma cell line MZ7 by MITF

2015-10-29 | GSE71798 | GEO

Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

Project description:Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. Yet how metabolism is implicated in specific phenotypes, and whether lineage-restricted mechanisms control key metabolic vulnerabilities remains poorly understood. In melanoma, down-regulation of the lineage addiction oncogene Microphthalmia-associated Transcription Factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, though how MITF promotes proliferation and suppresses invasion is poorly defined. Here we show that MITF is a lineage restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD), and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signalling, and an ATF4-mediated feedback-loop that maintains dedifferentiation. Our results reveal that MITF is a lineagespecific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype-switching, and highlight that cell phenotype dictates response to drugs targeting lipid metabolism.

2019-10-16 | GSE137390 | GEO

Identification of MITF-regulated genes in the human melanoma cell line Ma-Mel-15

Project description:We analyzed the transcriptional response of the human melanoma cell line Ma-Mel-15 either transfected with control siRNA (siNT = non-targeting siRNA) or transfected with siRNAs (pool of 4 active and independent siRNAs) directed against the melanocytic transcription factor and lineage oncogene MITF (Microphthalmia-associated transcription factor). The experiment was performed as biological duplicates and RNA was isolated 48 hours after siRNA transfection. We aimed to determine novel markers and pathways of melanoma cell plasticity. Total RNA was obtained from siRNA-treated Ma-Mel-15 melanoma cell lines and global gene expression profiling was done using the Illumina Human HT12 v4 platform.

2015-10-29 | E-GEOD-71881 | biostudies-arrayexpress

MITF WT and K243-mutant binding and expression [ChIP-Seq]

Project description:MITF is the master regulator of the melanocyte lineage and a melanoma lineage oncogene. It controls a wide range of target genes fulfilling many distinct functions, but relatively little is known about how its DNA-binding is regulated to select the correct target genes. The datasets presented here were used investigate the effects of MAPK signaling-induced MITF-acetylation on MITF activity in melanoma cells through ChIP-Seq of wild-type and acetyl-mutant MITF.

2021-02-12 | GSE77437 | GEO

Acetylation reprograms MITF target selectivity and residence time

Project description:Key to effective gene regulation in development and homeostasis is the ability of transcription factors to discriminate between different classes of binding sites. Yet how this is achieved is poorly understood. The microphthalmia-associated transcription factor MITF is a lineage-survival oncogene that plays a crucial role in melanoma and melanocyte development where it suppresses invasion but promotes both proliferation and differentiation. How MITF distinguishes between differentiation and proliferation-associated targets is unknown. Unexpectedly we show here that differentiation-associated target genes are characterized by low affinity MITF binding sites. MAPK signaling, a key driver of melanomagenesis downstream from BRAF and NRAS, promotes p300/CBP-mediated MITF acetylation at K206 to reduce preferentially DNA binding affinity at differentiation-associated targets. The results reveal a MAPK-driven acetylation switch that can trigger de-differentiation of melanocytes and provide a mechanistic explanation of why a human K206Q MITF mutation is associated with Waardenburg’s syndrome characterized by pigmentation abnormalities.

2023-08-07 | GSE137776 | GEO

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