Oncotarget: Aberrant epigenetic silencing of neuronatin - a frequent event in osteosarcoma

The cover for issue 20 of @Oncotarget features Figure 5, "Neuronatin protein expression is detectable in normal bone and cartilage tissues," by Saeed, et al.

It reported that the expression of NNAT was detectable in osteoblasts and chondrocytes of human bone, supporting a potential role in bone homeostasis.

Enforced expression of NNAT in human OS cells lacking endogenous expression resulted in a significant reduction in colony formation and in vitro migration compared to nonexpressor control cells.

Furthermore, NNAT expression was associated with increased cytotoxicity in OS cells from thapsigargin, an inhibitor of calcium reuptake into ER, and an inducer of the ER stress response.

Dr. Steven J. Kuerbitz Division of Pediatric Hematology/Oncology and the Rebecca D. Considine Research Institute at the Akron Children's Hospital as well as the Department of Pediatrics at Northeast Ohio Medical University said: "Osteosarcoma (OS) is the most common primary bone tumor in children, adolescents, and young adults."

"Osteosarcoma (OS) is the most common primary bone tumor in children, adolescents, and young adults"

- Dr. Steven J. Kuerbitz, Division of Pediatric Hematology/Oncology, the Rebecca D. Considine Research Institute at the Akron Children's Hospital, and the Department of Pediatrics at Northeast Ohio Medical University

Enforced expression of NNAT has been associated with decreased in vitro colony-forming efficiency and inhibition of proliferation in pituitary adenoma cells and decreased CFE in NSCLC, suggesting a potential tumor suppressor function in some cancers.

NNAT expression has been shown to induce adipocytic differentiation in mesenchymal cells and to induce apoptosis in pancreatic cells.

The roles ascribed to NNAT of induction of differentiation in cells of mesenchymal origin and silencing/suppression of neoplastic phenotypes in various cancers prompted us to explore a potential role in solid tumors in children, especially those of mesenchymal origin.

Figure 5: Neuronatin protein expression is detectable in normal bone and cartilage tissues. (A) Slides of mouse distal femur growth plate were stained with NNAT antibody and secondary antibody (left) or with secondary antibody alone (right). Magnification 20×. (B) Slides of femoral capital growth plate tissue from a 13 year-old human (left) and rib-end growth plate tissue from a 12-week-old human (right) were stained with NNAT antibody and secondary antibody. Magnification 20×.

The authors, therefore, studied the role of hypermethylation of NNAT promoter region on NNAT expression in OS cells and tested the effect of NNAT expression on the clonogenic and invasive capacity of OS cells in vitro.

Induction of NNAT expression in OS cells resulted in attenuated decay of intracellular calcium levels following mobilization from ER stores, and NNAT expression enhanced the cytotoxic effect of thapsagirgin, an inhibitor of SERCA2 and an inducer of endoplasmic reticulum stress in OS cells.

The Kuerbitz Research Team concluded in their Oncotarget Research paper that compiling a panel of such epigenetic targets and tailoring epigenetic modifier therapy to achieve optimal gene derepression may represent a new therapeutic modality for OS.

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DOI - https://doi.org/10.18632/oncotarget.27583

Full text - https://www.oncotarget.com/article/27583/text/

Correspondence to - Steven J. Kuerbitz - skuerbitz@akronchildrens.org

Keywords - osteosarcoma, DNA methylation, neuronatin, tumor suppressor genes

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