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

Publication ,  Journal Article
Bartholf DeWitt, S; Hoskinson Plumlee, S; Brighton, HE; Sivaraj, D; Martz, EJ; Zand, M; Kumar, V; Sheth, MU; Floyd, W; Spruance, JV; Hawkey, N ...
Published in: JCI Insight
September 8, 2022

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.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

September 8, 2022

Volume

7

Issue

17

Location

United States

Related Subject Headings

  • X-linked Nuclear Protein
  • Proto-Oncogene Proteins c-ets
  • Osteosarcoma
  • NF-kappa B
  • Integrin alphaVbeta3
  • Humans
  • Bone Neoplasms
  • Aggression
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
 

Citation

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Bartholf DeWitt, S., Hoskinson Plumlee, S., Brighton, H. E., Sivaraj, D., Martz, E. J., Zand, M., … Eward, W. C. (2022). Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding. JCI Insight, 7(17). https://doi.org/10.1172/jci.insight.151583
Bartholf DeWitt, Suzanne, Sarah Hoskinson Plumlee, Hailey E. Brighton, Dharshan Sivaraj, E. J. Martz, Maryam Zand, Vardhman Kumar, et al. “Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding.JCI Insight 7, no. 17 (September 8, 2022). https://doi.org/10.1172/jci.insight.151583.
Bartholf DeWitt S, Hoskinson Plumlee S, Brighton HE, Sivaraj D, Martz EJ, Zand M, et al. Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding. JCI Insight. 2022 Sep 8;7(17).
Bartholf DeWitt, Suzanne, et al. “Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding.JCI Insight, vol. 7, no. 17, Sept. 2022. Pubmed, doi:10.1172/jci.insight.151583.
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. Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding. JCI Insight. 2022 Sep 8;7(17).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

September 8, 2022

Volume

7

Issue

17

Location

United States

Related Subject Headings

  • X-linked Nuclear Protein
  • Proto-Oncogene Proteins c-ets
  • Osteosarcoma
  • NF-kappa B
  • Integrin alphaVbeta3
  • Humans
  • Bone Neoplasms
  • Aggression
  • 42 Health sciences
  • 32 Biomedical and clinical sciences