The Human T-cell Leukemia Virus type I basic leucine zipper factor upregulates the expression of the antioxidant Heme Oxygenase I,

Abstract

Adult T-cell Leukemia/Lymphoma (ATLL) is a resilient lymphoproliferative disease of CD4+ T-cells infected by the Human T-cell Leukemia Virus type I (HTLV-1), for which there are no effective treatments. Mounting evidence supports that the overexpression of antioxidants contributes to drug resistance in many types of cancer. One such antioxidant is the iron-recycling enzyme Heme Oxygenase (HMOX-1), which has been shown to enhance cancer cell survival upon exposure to stress-inducing agents. HMOX-1 expression is regulated by the small Maf AP1 proteins, which control transcription from promoter antioxidant response elements (AREs). A previous report, confirmed by our laboratory, shows that the HTLV-1 antisense-encoded basic leucine zipper factor, HBZ, interacts with small Mafs for recruitment to AREs in vitro. We questioned whether HBZ and small Mafs regulate the expression of antioxidants like HMOX-1 as a pro-survival strategy in ATLL cells. Our results show that HMOX-1 is overexpressed in ATLL cells in a manner dependent upon both HBZ and the small Mafs. These proteins were found to be present at an ARE in the promoter of HMOX-1 in vivo, and HBZ expression was observed to promote ARE transactivation in a small Maf-dependent manner. HMOX-1 is thought to be the main mediator of iron metabolism and functions in a cytoprotective capacity during oxidative stress. We observed that ATLL cells, as well as HBZ-expressing cells, exhibited resistance to iron-induced cytotoxicity, which was attenuated upon inhibition of HMOX-1 enzyme activity. Furthermore, HBZ expression was found to be important for maintaining ATLL cell redox state, as well as for maintaining cell viability in response to iron exposure. These findings support the possibility that HBZ and small Mafs may upregulate transcription at AREs to positively regulate some antioxidant response genes in ATLL cells, wherein these gene products may have cytoprotective effects in response to oxidative stress and may contribute to anti-cancer drug resistance.