Hypoxia-inducible factor-1 alpha as a therapeutic target for primary effusion lymphoma

• DOI: 10.1371/journal.ppat.1006628
• Publication Date: 2017-09-18T19:27:10Z
• Authors: Prabha Shrestha; David A. Davis; Ravindra P. Veeranna; Robert F. Carey; Coralie Viollet; Robert Yarchoan
• Keywords: Gene Expression Regulation, Viral; 0301 basic medicine; Mustard Compounds; Phenylpropionates; QH301-705.5; RC581-607; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia; 3. Good health; MicroRNAs; 03 medical and health sciences; Lymphoma, Primary Effusion; Humans; Immunologic diseases. Allergy; Biology (General); Antigens, Viral; Sarcoma, Kaposi; Research Article

Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma with poor prognosis caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Previous studies have revealed that HIF-1α, which mediates much of the cellular response to hypoxia, plays an important role in life cycle of KSHV. KSHV infection promotes HIF-1α activity, and several KSHV genes are in turn activated by HIF-1α. In this study, we investigated the effects of knocking down HIF-1α in PELs. We observed that HIF-1α knockdown in each of two PEL lines leads to a reduction in both aerobic and anaerobic glycolysis as well as lipid biogenesis, indicating that HIF-1α is necessary for maintaining a metabolic state optimal for growth of PEL. We also found that HIF-1α suppression leads to a substantial reduction in activation of lytic KSHV genes, not only in hypoxia but also in normoxia. Moreover, HIF-1α knockdown led to a decrease in the expression of various KSHV latent genes, including LANA, vCyclin, kaposin, and miRNAs, under both normoxic and hypoxic conditions. These observations provide evidence that HIF-1α plays an important role in PEL even in normoxia. Consistent with these findings, we observed a significant inhibition of growth of PEL in normoxia upon HIF-1α suppression achieved by either HIF-1α knockdown or treatment with PX-478, a small molecule inhibitor of HIF-1α. These results offer further evidence that HIF-1α plays a critical role in the pathogenesis of PEL, and that inhibition of HIF-1α can be a potential therapeutic strategy in this disease.