RT Journal Article
SR Electronic
T1 Targeting histone deacetylase activity to arrest cell growth and promote neural differentiation in Ewing sarcoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 191700
DO 10.1101/191700
A1 Souza, Bárbara Kunzler
A1 Costa Lopez, Patrícia Luciana da
A1 Menegotto, Pâmela Rossi
A1 Vieira, Igor Araujo
A1 Kersting, Nathalia
A1 Abujamra, Ana Lúcia
A1 Brunetto, André T.
A1 Brunetto, Algemir L.
A1 Gregianin, Lauro
A1 de Farias, Caroline Brunetto
A1 Thiele, Carol J.
A1 Roesler, Rafael
YR 2018
UL http://biorxiv.org/content/early/2018/01/16/191700.abstract
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.