Aberrant differentiation is a characteristic feature of neoplastic transformation, while
hypoxia in solid
tumors is believed to be linked to aggressive behavior and poor prognosis. However, the possible relationship between
hypoxia and differentiation in
malignancies remains poorly defined. Here we show that rat C6 and primary human
malignant glioma cells can be induced to differentiate into astrocytes by the well-known
adenylate cyclase activator
forskolin. However,
hypoxia-inducible factor-1alpha expression stimulated by the
hypoxia mimetics
cobalt chloride or
deferoxamine blocks this differentiation and this effectiveness is reversible upon withdrawal of the
hypoxia mimetics. Importantly, knockdown of
hypoxia inducible factor-1alpha by RNA interference restores the differentiation capabilities of the cells, even in the presence of
cobalt chloride, whereas stabilization of
hypoxia-inducible factor-1alpha through retarded ubiquitination by von Hippel-Lindau tumor suppressor gene silence abrogates the induced differentiation. Moreover, targeting of HIF-1 using
chetomin, a disrupter of HIF-1 binding to its transcriptional co-activator
CREB-binding protein (CBP)/p300, abolishes the differentiation-inhibitory effect of
hypoxia-inducible factor-1alpha. Administration of
chetomin in combination with
forskolin significantly suppresses
malignant glioma growth in an in vivo xenograft model. Analysis of 95 human
glioma tissues revealed an increase of
hypoxia-inducible factor-1alpha
protein expression with progressing
tumor grade. Taken together, these findings suggest a key signal transduction pathway involving
hypoxia-inducible factor-1alpha that contributes to a differentiation defect in
malignant gliomas and sheds new light on the differentiation
therapy of solid
tumors by targeting
hypoxia-inducible factor-1alpha.