congresos y reuniones científicas
Glucocorticoid receptor regulates bcl-x expression in leukemic cells
SILBERMINS, M.; PECCI, A.; ROCHA VIEGAS, L.
Workshop; SISTAM 2012; 2012
The leukaemias are malignant diseases of haematopoietic cells in which the proper balance between proliferation, differentiation and apoptosis is no longer operative. Glucocorticoids have been identified as potent regulators controlling cell turnover in a tissue- and cell-specific manner, with a great clinical relevance. Synthetic glucocorticoids, like dexametasone (Dex), are frequently used in the treatment of hematopoietic diseases due to its proapoptotic properties, and although their mechanism of action on leukemic cells is unclear, these steroid hormones could represent an alternative and promising theraphy. The main goal of this project is to study the epigenetic events involved on the glucocorticoid receptor (GR)-mediated apoptosis in human leukemic cells. Our results showed that U937 cell line undergoes more than a 20% cell death after 72 h of 50 nM Dex treatment, and this correlates with the downregulation of the antiapoptotic isoform Bcl-XL. We also evaluated the role of ASH2L (K4H3 methylase activity) and NCOA6 (steroid receptor coactivator) proteins as putative epigenetic modulators involved in the glucocorticoid response. Interestingly, stable ASH2L and NCOA6 knockdown U937 cells (shASH2 and shNCOA6) showed a delayed onset of apoptosis upon Dex treatment (15% and 10% respectively), when compared to the mock knockdown cells (shRandom). Also the expression of Bcl-X resulted unaffected in U937 shASH2 and shNCOA6, suggesting that both ASH2L and NCOA6 are necessary for proper cell death in response to glucocorticoids in these cells.