Inhibition of histone deacetylase 4 reduces glioblastoma tumor growth in vivothe role of deacetylases inhibitors and notch signaling pathway in the treatment of glioblastomas

Resumen

Glioblastomas (GBM) are the most common and malignant brain tumors in adults. Histone deacetylases are a group of enzymes that play an important role in the regulation of many genes. In this study, we have demonstrated that knocking down HDAC4 expression decreases human GBM-derived neurosphere growth and invasion in vitro and their propagation in vivo through targeting cancer stem cells. We have also seen that HDAC4 expression is regulated by the Notch signaling pathway in GBM neurospheres, and HDAC4 expression correlates with Notch activity in primary GBM samples. Knockdown of HDAC4 expression also decreases transgenic mouse (Nf1-/-;p53-/-) GBM-derived neurosphere propagation both in vitro and in vivo through reducing cancer stem cell population. Pharmacological inhibition of HDAC4 activity by panobinostat depletes cancer stem cells in human derived-GBM neurospheres and prolongs the survival in mice bearing intracranial xenografts. HDAC4 inhibition depletes cancer stem cells through genes that regulate cancer stem cell proliferation and apoptosis, such as p21. The Notch signaling pathway regulates HDAC4 expression at transcription level through c-Myc binding to the promoter region of HDAC4. Finally, we demonstrated that HDAC4 plays an important role not only in cancer cells, but also in normal brain cells, such as human astrocytes.