Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility

Cell. 2016 Jul 14;166(2):328-342. doi: 10.1016/j.cell.2016.05.052. Epub 2016 Jun 30.

Abstract

Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Mice
  • NFI Transcription Factors / genetics
  • NFI Transcription Factors / metabolism*
  • Neoplasm Metastasis / pathology*
  • Promoter Regions, Genetic
  • Small Cell Lung Carcinoma / genetics
  • Small Cell Lung Carcinoma / metabolism
  • Small Cell Lung Carcinoma / pathology*
  • Up-Regulation

Substances

  • NFI Transcription Factors
  • Nfib protein, mouse