The twist box domain is required for Twist1-induced prostate cancer metastasis. Academic Article uri icon

Overview

MeSH

  • Amino Acid Substitution
  • Animals
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins
  • Humans
  • Male
  • Mice, Nude
  • Neoplasm Invasiveness
  • Promoter Regions, Genetic
  • Transcriptional Activation

MeSH Major

  • Neoplasm Metastasis
  • Nuclear Proteins
  • Prostatic Neoplasms
  • Protein Structure, Tertiary
  • Twist-Related Protein 1

abstract

  • Twist1, a basic helix-loop-helix transcription factor, plays a key role during development and is a master regulator of the epithelial-mesenchymal transition (EMT) that promotes cancer metastasis. Structure-function relationships of Twist1 to cancer-related phenotypes are underappreciated, so we studied the requirement of the conserved Twist box domain for metastatic phenotypes in prostate cancer. Evidence suggests that Twist1 is overexpressed in clinical specimens and correlated with aggressive/metastatic disease. Therefore, we examined a transactivation mutant, Twist1-F191G, in prostate cancer cells using in vitro assays, which mimic various stages of metastasis. Twist1 overexpression led to elevated cytoskeletal stiffness and cell traction forces at the migratory edge of cells based on biophysical single-cell measurements. Twist1 conferred additional cellular properties associated with cancer cell metastasis including increased migration, invasion, anoikis resistance, and anchorage-independent growth. The Twist box mutant was defective for these Twist1 phenotypes in vitro. Importantly, we observed a high frequency of Twist1-induced metastatic lung tumors and extrathoracic metastases in vivo using the experimental lung metastasis assay. The Twist box was required for prostate cancer cells to colonize metastatic lung lesions and extrathoracic metastases. Comparative genomic profiling revealed transcriptional programs directed by the Twist box that were associated with cancer progression, such as Hoxa9. Mechanistically, Twist1 bound to the Hoxa9 promoter and positively regulated Hoxa9 expression in prostate cancer cells. Finally, Hoxa9 was important for Twist1-induced cellular phenotypes associated with metastasis. These data suggest that the Twist box domain is required for Twist1 transcriptional programs and prostate cancer metastasis. Targeting the Twist box domain of Twist1 may effectively limit prostate cancer metastatic potential. ©2013 AACR.

publication date

  • November 2013

has subject area

  • Amino Acid Substitution
  • Animals
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins
  • Humans
  • Male
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Nuclear Proteins
  • Promoter Regions, Genetic
  • Prostatic Neoplasms
  • Protein Structure, Tertiary
  • Transcriptional Activation
  • Twist-Related Protein 1

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3833995

Digital Object Identifier (DOI)

  • 10.1158/1541-7786.MCR-13-0218-T

PubMed ID

  • 23982216

Additional Document Info

start page

  • 1387

end page

  • 1400

volume

  • 11

number

  • 11