Different Roles of Sp Family Members in HIV-1 Tat-Mediated Manganese Superoxide Dismutase Suppression in Hepatocellular Carcinoma Cells

Abstract

The expression of manganese superoxide dismutase (MnSOD) is regulated by agents associated with cancer development. It has been shown that infection with the human immunodeficiency virus type 1 (HIV-1) is associated with the development of liver cancer and that the transactivating transcriptional factor (Tat) of human HIV-1 reduces the expression of MnSOD in several cell types. However, the role of Tat in the expression of MnSOD in hepatocellular carcinoma is unknown. Furthermore, the precise mechanisms whereby Tat suppresses MnSOD expression in hepatocellular carcinoma cells remain unclear. In this report, we build on our original observations that Tat changes the distribution of Sp family members on the MnSOD promoter, which accounts for Tat-dependent changes in basal expression. In hepatic cells, Tat expression upregulates Sp1/Sp3, which play different roles in regulating MnSOD transcription. While overexpression of Sp1 stimulates, overexpression of Sp3 represses transcriptional activity. The transcription repression effect of Sp3 is not due to Sp3 competing for the binding site with Sp1 because only the full-length Sp3 but not the truncated Sp3 suppresses MnSOD promoter activity. These findings suggest a novel mechanism by which Tat modulates the repression of the MnSOD gene and establish a link between HIV infection and liver cancer.

The HIV-Tat protein interacts with Sp3 transcription factor and inhibits its binding to a distal site of the sod2 promoter in human pulmonary artery endothelial cells

“…Redox imbalance is a critical factor in the HIV life cycle and well established consequence of HIV infection and oxidative stress is a unifying factor across a vast array of HIV associated co-morbidities. In previous studies, Tat has been demonstrated to have a repressive effect on SOD2 expression by proxy of altering Sp1/Sp3 binding to the proximal sod2 promoter [44], though the reliance on artificial promoter constructs as well as transformed cell lines has left an incomplete picture of how Tat may interact with these transcription factors and effect SOD2 in more physiologically relevant systems. Here, we have observed that Tat indeed alters Sp1/Sp3 activity and as such, modulates endogenous SOD2 expression in primary HPAEC.…”

Methamphetamine Augments Concurrent Astrocyte Mitochondrial Stress, Oxidative Burden, and Antioxidant Capacity: Tipping the Balance in HIV-Associated Neurodegeneration

“…Other studies also demonstrate HIV-1 gp120 mediated ER stress and apoptosis in simian virus 40 transformed astrocytes (SVGA) (Shah et al 2016). HIV-1 transactivator of transcription (Tat) increases mitophagy, as measured by LC3 cleavage, and is associated antioxidant depletion, a sign of oxidative stress (De Simone et al 2016; Porntadavity et al 2005). Further, several antiretroviral drugs interfere with physiological mitochondrial function, contributing to oxidative stress.…”