Reactivation of silenced α-N-catenin induces retinoic acid sensitivity in neuroblastoma cells

Background: High-risk neuroblastoma remains the most difficult pediatric solid tumor to treat and is associated with chemotherapy and radiation resistance that may be secondary to epigenetic modifica-tions. We have previously found that alpha-N-catenin, a cell-adhesion protein encoded by the gene CTNNA2, plays a tumor suppressor role in neuroblastoma by inhibiting the NF-kappa B signaling pathway. A subset of neuroblastoma tumors that lack alpha-N-catenin are resistant to all-trans retinoic acid. However, the mechanism of CTNNA2 silencing in neuroblastoma remains unknown. Herein, we sought to determine the mechanism of alpha-N-catenin silencing in neuroblastoma. Methods: Two human neuroblastoma cell lines, SK-N-AS and BE(2)-C, were stably transfected with a plasmid expressing CTNNA2. Both cell lines were treated with the histone deacetylase inhibitor Trichostatin A alone and in combination with retinoic acid. Cell survival and colony formation were measured. Cellular differentiation and expression of cell survival signaling pathways were analyzed. Immunoblotting and reverse transcription quantitative polymerase chain reaction were used to examine protein and messenger RNA expression. Results: Retinoic acid treatment induced cellular differentiation and inhibited cellular proliferation in BE(2)-C cells but did not induce differentiation in SK-N-AS cells. Re-expression of alpha-N-catenin enhanced the sensitivity to retinoic acid-induced cell growth arrest and downregulated key cell survival pathways in both cell lines. Trichostatin A treatment induced CTNNA2 expression in SK-N-AS cells, and combination treatment with Trichostatin A induced retinoic acid sensitivity in retinoic acid-resistant cells. Conclusion: Re-expression of alpha-N-catenin in retinoic acid-resistant cells induced sensitivity to retinoic acid treatment and is controlled epigenetically via histone deacetylase. alpha-N-catenin is a potential biomarker for retinoic acid sensitivity and combination treatment with Trichostatin A and retinoic acid may improve survival among children with high-risk, retinoic acid-resistant neuroblastoma. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

In this study, re-expression of alpha-N-catenin in retinoic acid-resistant neuroblastoma cells was found to enhance sensitivity to retinoic acid treatment, which is epigenetically controlled by histone deacetylase. This discovery suggests that combination treatment with Trichostatin A and retinoic acid may improve survival among children with high-risk, retinoic acid-resistant neuroblastoma.