Loss of the chromatin remodeler, ATRX, promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin receptor binding

Abstract

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 dataset 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 alpha thalassemia mental retardation syndrome.

ATRX and Its Prognostic Significance in Soft Tissue Sarcoma

“…ATRX is one of the most frequently mutated genes in STS, along with TP53 and RB1 [ 4 ]. ATRX has wide-ranging cellular consequences, including a role in chromatin remodeling [ 30 ], telomere elongation [ 5 , 12 , 16 , 31 , 32 ], regulation of transcription, DNA repair, mitotic recombination [ 33 ], NF-kB signaling, and invasion [ 5 ]. Additional work has demonstrated that ATRX plays important roles in epigenetic regulation, modulating PRC2 activity [ 21 ].…”

“…With the advancement in molecular profiling and next-generation sequencing techniques, STS can be classified into unique subgroups [ 3 ], and such groupings may provide insight into prognostic or therapeutic insights for these patients. While the genomic underpinnings of STS are complex, three genes are consistently mutated in STS: TP53, RB1, and ATRX [ 4 , 5 ]. Although TP53 [ 6 – 8 ] and RB1 [ 9 ] are well-known tumor suppressors across many cancer types, ATRX is less well characterized.…”

“…NF-κB activation induces expression of antiapoptotic genes and promotes multiple features associated with a prometastatic phenotype, such as cell growth, angiogenesis, and epithelialmesenchymal transition [18][19][20]. In osteosarcoma, mutations in ATRX lead to upregulation of NF-κB, extracellular matrix remodeling, increased B3 integrin expression, and more aggressive tumor cell phenotypes, including increased growth, migration, invasion, and metastasis [5]. In STS, ATRX loss is associated with increased chromosomal and mitotic instability, as well as a reduction in disease-specifc survival [21].…”