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

Abstract

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-1α 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-1α and induced autophagy initially, while extended incubation with the drug resulted in inhibition of HIF-1α. We tested the hypothesis that PCI-24781- induced autophagy is mediated by HIF-1α and that inhibition of HIF-1α 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.

CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

“…Yuan et al demonstrated that Tenovin-6, a small molecular compound which can activate p53 and inhibit the protein deacetylase activity of purified SIRT1/2/3, can inhibit cell survival of DLBCL via blocking autophagy [50]. With respect to cancer, autophagy is often associated with a pro-survival phenotype [53,54]. In our study, we found that CUL4B could promote cell growth in DLBCL.…”

“…Extensive number of genes and proteins were confirmed to interference autophagy and further promote tumorigenesis through regulation of different mechanisms and signal pathways, including PI3K/AKT/mTOR and JNK signaling pathways [55][56][57][58]. Aberrant activation of signaling pathways led to activation of multiple downstream effectors, including those involved in growth, survival, and autophagy [20,54]. Previously studies showed that blocking of the PI3K/AKT/mTOR and JNK signaling could reduce cell survival and function of lymphocytes [59][60][61][62], potentially regarded as a therapeutic method for DLBCL.…”

Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer

“…It is stabilized under hypoxia and supports the Warburg effect [ 16 , 47 ]. In tumor cells it can be activated also under normoxic conditions (“pseudohypoxia”) [ 14 , 48 , 49 ].…”

Targeted Therapies in Adult B-Cell Malignancies

“…Anti-CXCR4 or CXCL12R (plerixafor and others), anti-CCR5 or CCL5R (maraviroc), inhibitors of survival/proliferation factors, that is, IL6, BAFF/APRIL, and others, but also inhibitors of osteoprotegerin, and a receptor for both RANKL and TNF-related apoptosis-inducing ligand/Apo2 (TRAIL) may represent new targets for cancer therapy [ 49 , 112 , 113 ]. The complex CXCL12/CXCR4 is implicated in biological mechanisms of several B-cell malignancies, particularly for CLL, MM, and lymphoma [ 112 ].…”