Abstract
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). We recently reported that abacavir, an anti-HIV-1 drug, potently and selectively kills ATL cells. This effect was attributed to the reduced expression of tyrosyl-DNA-phosphodiesterase 1 (TDP1), a DNA repair enzyme, in ATL cells. However, the molecular mechanism underlying the downregulation of TDP1 in ATL cells remains elusive. Here we identified the core promoter of the TDP1 gene, which contains a conserved nuclear respiratory factor 1 (NRF-1) binding site. Overexpression of NRF-1 increased TDP1-promoter activity, whereas the introduction of dominant-negative NRF-1 repressed such activity. Overexpression of NRF-1 also upregulated endogenous TDP-1 expression, while introduction of shNRF-1 suppressed TDP1 in Jurkat T cells, making them susceptible to abacavir. These results indicate that NRF-1 is a positive transcriptional regulator of TDP1-gene expression. Importantly, we revealed that HTLV-1 bZIP factor (HBZ) protein which is expressed in all ATL cases physically interacts with NRF-1 and inhibits the DNA-binding ability of NRF-1. Taken together, HBZ suppresses TDP1 expression by inhibiting NRF-1 function in ATL cells. The HBZ/NRF-1/TDP1 axis provides new therapeutic targets against ATL and might explain genomic instability leading to the pathogenesis of ATL.
Highlights
Adult T-cell leukemia (ATL) is a neoplastic disease of CD4+ T cells caused by human T-cell leukemia virus type 1 (HTLV-1)[1]
To search for the cause of the downregulation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in ATL cells, we first investigated whether the TDP1 gene was mutated or if its promoter was epigenetically modified in ATL cells
TDP1 expression had a significant correlation with NRF-1 expression in the NCI-60 human-tumor cell-line panel (Fig. 1E) as well as in the Cancer Cell Line Encyclopedia (Fig. 1F)
Summary
Adult T-cell leukemia (ATL) is a neoplastic disease of CD4+ T cells caused by human T-cell leukemia virus type 1 (HTLV-1)[1]. Suppression of HBZ gene transcription by short interfering RNA inhibits the proliferation of ATL cells[7]. HBZ promotes the development of T-cell lymphomas and inflammatory diseases in transgenic mice[8] This indicates that HBZ, in addition to Tax, plays an important role in the development of ATL. NRF-1, a master regulator of mitochondria[14], is reported as one of seven identified transcription factors whose binding sites are most frequently found in the proximal promoters of ubiquitously expressed genes[15]. We demonstrate that HBZ suppresses the transcription of TDP1 by interfering with the DNA-binding activity of NRF-1. These results indicate that HBZ suppresses the NRF-1-mediated expression of TDP1, leading to the high susceptibility of ATL cells to ABC
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