Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding.

Journal Article (Journal Article)

Osteosarcoma (OS) is a lethal disease with few known targeted therapies. Here, we show that decreased ATRX expression is associated with more aggressive tumor cell phenotypes, including increased growth, migration, invasion, and metastasis. These phenotypic changes correspond with activation of NF-κB signaling, extracellular matrix remodeling, increased integrin αvβ3 expression, and ETS family transcription factor binding. Here, we characterize these changes in vitro, in vivo, and in a data set of human OS patients. This increased aggression substantially sensitizes ATRX-deficient OS cells to integrin signaling inhibition. Thus, ATRX plays an important tumor-suppression role in OS, and loss of function of this gene may underlie new therapeutic vulnerabilities. The relationship between ATRX expression and integrin binding, NF-κB activation, and ETS family transcription factor binding has not been described in previous studies and may impact the pathophysiology of other diseases with ATRX loss, including other cancers and the ATR-X α thalassemia intellectual disability syndrome.

Full Text

Duke Authors

Cited Authors

  • Bartholf DeWitt, S; Hoskinson Plumlee, S; Brighton, HE; Sivaraj, D; Martz, EJ; Zand, M; Kumar, V; Sheth, MU; Floyd, W; Spruance, JV; Hawkey, N; Varghese, S; Ruan, J; Kirsch, DG; Somarelli, JA; Alman, B; Eward, WC

Published Date

  • September 8, 2022

Published In

Volume / Issue

  • 7 / 17

PubMed ID

  • 36073547

Pubmed Central ID

  • PMC9536280

Electronic International Standard Serial Number (EISSN)

  • 2379-3708

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.151583

Language

  • eng

Conference Location

  • United States