Paradoxical Regulation of Hypoxia Inducible Factor-1alpha (HIF-1alpha) by Histone Deacetylase Inhibitor in Diffuse Large B-Cell Lymphoma

Bhalla, S.; Evens, A. M.; Prachand, S.; Schumacker, P. T.; Gordon, L. I.

PLoS One. 2013 Dec 7; 8(11):e81333


Hypoxia inducible factor (HIF) is important in cancer, as it regulates various oncogenic genes as well as genes involved in cell survival, proliferation, and migration. Elevated HIF-1 protein promotes a more aggressive tumor phenotype, and greater HIF-1 expression has been demonstrated to correlate with poorer prognosis, increased risk of metastasis and increased mortality. Recent reports suggest that HIF-1 activates autophagy, a lysosomal degradation pathway which may promote tumor cell survival. We show here that HIF-1alpha expression is constitutively active in multiple diffuse large B cell lymphoma (DLBCL) cell lines under normoxia and it is regulated by the PI3K/AKT pathway. PCI-24781, a pan histone deacetylase inhibitor (HDACI), enhanced accumulation of HIF-1alpha and induced autophagy initially, while extended incubation with the drug resulted in inhibition of HIF-1alpha. We tested the hypothesis that PCI-24781- induced autophagy is mediated by HIF-1alpha and that inhibition of HIF-1alpha in these cells results in attenuation of autophagy and decreased survival. We also provide evidence that autophagy serves as a survival pathway in DLBCL cells treated with PCI-24781 which suggests that the use of autophagy inhibitors such as chloroquine or 3-methyl adenine in combination with PCI-24781 may enhance apoptosis in lymphoma cells.

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