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Screening for Melanoma Modifiers using a Zebrafish Autochthonous Tumor Model
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The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

Elizabeth A Coe1, Jennifer Y Tan2, Michael Shapiro1

  • 1Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom.

Plos Genetics
|December 28, 2019
PubMed

Insights

Long noncoding RNAs (lncRNAs) are newly identified regulators in melanoma. This study reveals lncRNAs within MITF-SOX10 networks, including DIRC3, a tumor suppressor influencing melanoma growth and patient survival.

Area of Science:

  • Melanoma research
  • Cancer epigenetics
  • Noncoding RNA biology

Background:

  • MITF and SOX10 transcription factors are key regulators of melanoma progression.
  • The role of long noncoding RNAs (lncRNAs) in melanoma's MITF-SOX10 transcriptional programs is largely unknown.

Purpose of the Study:

  • To investigate the function of lncRNAs within MITF-SOX10 transcriptional networks in melanoma.
  • To identify novel melanoma-associated lncRNAs regulated by MITF-SOX10.

Main Methods:

  • Identification of candidate melanoma-associated lncRNAs co-occupied by MITF-SOX10 at active enhancer-like regions.
  • Functional analysis of the lncRNA Disrupted In Renal Carcinoma 3 (DIRC3) in human melanoma cells.
  • Assessment of DIRC3 expression in melanoma patients and correlation with survival.

Main Results:

  • 245 candidate melanoma-associated lncRNAs were identified, co-occupied by MITF-SOX10.
  • DIRC3 functions as a tumor suppressor, with its depletion increasing anchorage-independent growth in melanoma cells.
  • Low DIRC3 expression in melanoma patients correlates with decreased survival.
  • DIRC3 activates neighboring IGFBP5 tumor suppressor expression by modulating chromatin and suppressing SOX10 binding.
  • DIRC3-IGFBP5 regulation impacts cancer-associated gene expression and anchorage-independent growth.

Conclusions:

  • lncRNAs are integral components of MITF-SOX10 networks in melanoma, acting as both downstream mediators and feedback regulators.
  • DIRC3 is a novel MITF-SOX10-regulated tumor suppressor lncRNA with clinical significance in melanoma.
  • These lncRNAs represent a new class of melanoma regulators and potential therapeutic targets.

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