Loss of the chromatin remodeler, ATRX, promotes aggressive features of osteosarcomas and activates NF-kB signaling and integrin receptor binding

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-?B signaling, extracellular matrix remodeling, increased integrin avß3 expression, and ETS family transcription factor binding. However, 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 a new therapeutic vulnerability. The relationship of ATRX expression with integrin binding, NF-?B activation, and ETS family transcription factor binding has not been noted in previous studies, but may impact other known diseases with ATRX loss, including other cancers and the ATR-X alpha thalassemia mental retardation syndrome. Overall design: RNA-Seq and ATAC-Seq profiles of 143B human osteosarcomas cells stably transduced with either a non-silencing GFP shRNA or one of two independent shRNA constructs targeting ATRX.