PT  - JOURNAL ARTICLE
AU  - Souza, Bárbara Kunzler
AU  - Costa Lopez, Patrícia Luciana da
AU  - Menegotto, Pâmela Rossi
AU  - Vieira, Igor Araujo
AU  - Kersting, Nathalia
AU  - Abujamra, Ana Lúcia
AU  - Brunetto, André T.
AU  - Brunetto, Algemir L.
AU  - Gregianin, Lauro
AU  - de Farias, Caroline Brunetto
AU  - Thiele, Carol J.
AU  - Roesler, Rafael
TI  - Targeting histone deacetylase activity to arrest cell growth and promote neural differentiation in Ewing sarcoma
AID  - 10.1101/191700
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 191700
4099  - http://biorxiv.org/content/early/2018/01/16/191700.short
4100  - http://biorxiv.org/content/early/2018/01/16/191700.full
AB  - There is an urgent need for advances in the treatment of Ewing sarcoma (EWS), an aggressive childhood tumor with possible neuroectodermal origin. Inhibition of histone deacetylases (HDAC) can revert aberrant epigenetic states and reduce growth in different experimental cancer types. Here, we investigated whether the potent HDAC inhibitor, sodium butyrate (NaB) has the ability to reprogram EWS cells towards a more differentiated state and affect their growth and survival. Exposure of two EWS cell lines to NaB resulted in rapid and potent inhibition of HDAC activity (1 h, IC50 1.5 mM) and a significant arrest of cell cycle progression (72 h, IC50 0.68-0.76 mM), marked by G0/G1 accumulation. Delayed cell proliferation and reduced colony formation ability were observed in EWS cells after long-term culture. NaB-induced effects included suppression of cell proliferation accompanied by reduced transcriptional expression of the EWS-FLI1 fusion oncogene, decreased expression of key survival and pluripotency-associated genes, and re-expression of the differentiation neuronal marker ²III-tubulin. Finally, NaB reduced c-MYC levels and impaired survival in putative EWS cancer stem cells. Our findings support the use of HDAC inhibition as a strategy to impair cell growth and survival and to reprogram EWS tumors towards differentiation. These results are consistent with our previous studies indicating that HDis can inhibit the growth and modulate differentiation of cells from other types of childhood pediatric tumors possibly originating from neural stem cells.