Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state

Nat Commun. 2015 Apr 9;6:6683. doi: 10.1038/ncomms7683.

Abstract

Transcriptional reprogramming of proliferative melanoma cells into a phenotypically distinct invasive cell subpopulation is a critical event at the origin of metastatic spreading. Here we generate transcriptome, open chromatin and histone modification maps of melanoma cultures; and integrate this data with existing transcriptome and DNA methylation profiles from tumour biopsies to gain insight into the mechanisms underlying this key reprogramming event. This shows thousands of genomic regulatory regions underlying the proliferative and invasive states, identifying SOX10/MITF and AP-1/TEAD as regulators, respectively. Knockdown of TEADs shows a previously unrecognized role in the invasive gene network and establishes a causative link between these transcription factors, cell invasion and sensitivity to MAPK inhibitors. Using regulatory landscapes and in silico analysis, we show that transcriptional reprogramming underlies the distinct cellular states present in melanoma. Furthermore, it reveals an essential role for the TEADs, linking it to clinically relevant mechanisms such as invasion and resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cellular Reprogramming / genetics
  • Chromatin / chemistry
  • Chromatin / metabolism
  • DNA Methylation
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Gene Regulatory Networks*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Neoplasm Invasiveness
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • SOXE Transcription Factors / genetics
  • SOXE Transcription Factors / metabolism
  • Signal Transduction
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptome*

Substances

  • Antineoplastic Agents
  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • Nuclear Proteins
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • SOX10 protein, human
  • SOXE Transcription Factors
  • TEAD1 protein, human
  • Transcription Factor AP-1
  • Transcription Factors