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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70177 | GEO | 2016/01/15

SECONDARY ACCESSION(S): PRJNA287798

REPOSITORIES: GEO

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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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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.

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