The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30II and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma

Highlights: • The HTLV-1 oncoproteins Tax and HBZ induce oxidative damage and autophagy/mitophagy. • HTLV-1 p30II activates TIGAR and suppresses Tax/HBZ-induced ROS and cytotoxicity. • HTLV-1 p30II cooperates with Tax and HBZ and induces oncogenic foci-formation. • TIGAR is highly expressed in HTLV-1+ xenograft tumors with oncogene dysregulation. • The expression of TIGAR in HTLV-1+ lymphoma tissues is associated with angiogenesis. The human T-cell leukemia virus type-1 (HTLV-1) is an oncoretrovirus that infects and transforms CD4+ T-cells and causes adult T-cell leukemia/lymphoma (ATLL) –an aggressive lymphoproliferative disease that is highly refractive to most anticancer therapies. The HTLV-1 proviral genome encodes several regulatory products within a conserved 3′ nucleotide sequence, known as pX; however, it remains unclear how these factors might cooperate or dynamically interact in virus-infected cells. Here we demonstrate that the HTLV-1 latency-maintenance factor p30^II induces the TP53-induced glycolysis and apoptosis regulator (TIGAR) and counters the oxidative stress, mitochondrial damage, and cytotoxicity caused by the viral oncoproteins Tax and HBZ. The p30^II protein cooperates with Tax and HBZ and enhances their oncogenic potential in colony transformation/foci-formation assays. Further, we have shown that TIGAR is highly expressed in HTLV-1-induced tumors associated with oncogene dysregulation and increased angiogenesis in an in vivo xenograft model of HTLV-1-induced T-cell lymphoma. These findings provide the first evidence that p30^II likely collaborates as an ancillary factor for the major oncoproteins Tax and HBZ during retroviral carcinogenesis.