Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding
Suzanne Bartholf DeWitt, Sarah Hoskinson Plumlee, Hailey E. Brighton, Dharshan Sivaraj, E.J. Martz, Maryam Zand, Vardhman Kumar, Maya U. Sheth, Warren Floyd, Jacob V. Spruance, Nathan Hawkey, Shyni Varghese, Jianhua Ruan, David G. Kirsch, Jason A. Somarelli, Ben Alman, William C. Eward
Suzanne Bartholf DeWitt, Sarah Hoskinson Plumlee, Hailey E. Brighton, Dharshan Sivaraj, E.J. Martz, Maryam Zand, Vardhman Kumar, Maya U. Sheth, Warren Floyd, Jacob V. Spruance, Nathan Hawkey, Shyni Varghese, Jianhua Ruan, David G. Kirsch, Jason A. Somarelli, Ben Alman, William C. Eward
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Research Article Oncology

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

Authors

Suzanne Bartholf DeWitt, Sarah Hoskinson Plumlee, Hailey E. Brighton, Dharshan Sivaraj, E.J. Martz, Maryam Zand, Vardhman Kumar, Maya U. Sheth, Warren Floyd, Jacob V. Spruance, Nathan Hawkey, Shyni Varghese, Jianhua Ruan, David G. Kirsch, Jason A. Somarelli, Ben Alman, William C. Eward

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Figure 5

ATRX KO increases nuclear expression of NF-κB transcription factors, and an analysis of ATRX chromatin binding motifs highlights common ETS transcription factor family binding motifs.

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ATRX KO increases nuclear expression of NF-κB transcription factors, an...
(A) NF-κB ELISA shows increased relative nuclear expression of this family of transcription factors (TFs) with ATRX KO when comparing nuclear extracts from both the 143B and MG-63 WT or KO cell lines (Multiple t tests). Statistically significant comparisons for 143B: p65, P = 0.0004; p50, P = 0.000009; cRel, P = 0.04; p52, P = 0.009; n = 3 replicates for each cell type and TF. Statistically significant comparisons for MG-63: p65, P = 0.01; RelB, P = 0.024; n = 3 replicates for each cell type and TF. (B) Top differentially deviated binding motifs found with ATRX shRNA knockdown in the 143B cell line most closely resemble the ETS transcription factor family binding motifs.