KSHV hijacks FoxO1 to promote cell proliferation and cellular transformation by antagonizing oxidative stress

Abstract

AbstractReactive oxygen species (ROS) are a group of a highly short‐lived molecules that control diverse behaviors of cells. Normal cells maintain ROS balance to ensure their functions. Because of oncogenic stress, cancer cells often have excessive ROS, also known as oxidative stress, which are often counteracted by enhanced antioxidant systems to maintain redox homeostasis. Kaposi's sarcoma‐associated herpesvirus (KSHV) is an oncogenic virus associated with Kaposi's sarcoma (KS), which manifests hyper inflammation and oxidative stress as the hallmarks. We have previously shown that excessive ROS can disrupt KSHV latency by inducing viral lytic replication, leading to cell death. Paradoxically, most KS tumor cells are latently infected by KSHV in a highly inflammatory and oxidative stress tumor microenvironment, which is in part due to the activation of alternative complement and TLR4 pathways, indicating the existence of an enhanced antioxidant defense system in KS tumor cells. In this study, we show that KSHV upregulates antioxidant genes, including SOD2 and CAT by hijacking the forkhead box protein O1 (FoxO1), to maintain intracellular ROS level. Moreover, the fine‐tuned balance of ROS level in KSHV‐transformed cells is essential for cell survival. Consequently, KSHV‐transformed cells are extremely sensitive to exogenous ROS insult such as treatment with a low level of hydrogen peroxide (H2O2). Either chemical inhibition or knockdown of FoxO1 by short interfering RNAs decreases the expression of antioxidant genes and subsequently increases the intracellular ROS level in KSHV‐transformed cells, resulting in the inhibition of cell proliferation and colony formation in soft agar. Mechanistically, KSHV‐encoded microRNAs and vFLIP upregulate FoxO1 by activating the NF‐κB pathway. These results reveal a novel mechanism by which an oncogenic virus counteracts oxidative stress by upregulating FoxO1, which is essential for KSHV‐induced cell proliferation and cellular transformation. Therefore, FoxO1 might be a potential therapeutic target for KSHV‐related malignancies.