Hypoxia inducible factor‐1α suppresses Peroxiredoxin 3 expression to promote proliferation of CCRCC cells

Abstract

a b s t r a c tPeroxiredoxin 3 (Prx3) is a mitochondrial member of the antioxidant family of thioredoxin peroxidases that uses mitochondrial thioredoxin 2 as a source of reducing equivalents to scavenge hydrogen peroxide (H 2 O 2 ). Here, we report that the protein levels of Prx3 are significantly reduced in VHL-deficient clear cell renal cell carcinoma (CCRCC). Furthermore, stabilization of HIF-1a protein, caused either by VHL deficiency under normoxia, or by hypoxia, significantly reduced Prx3 expression. Luciferase-reporter and chromatin-immunoprecipitation assays indicated that HIF-1a binds to the hypoxia-responsive elements of PRDX3 promoter and represses its transcription. Finally, shRNAbased assays suggested that Prx3 downregulation is required for the HIF-1a-dependent proliferation of CCRCC cells. Taken together, our results shed new light onto the mechanism of HIF-1a-dependent proliferation in CCRCC cells.

Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

“…PRDX3 is a mitochondrial-specific protein with one thioredoxin domain involved in cell redox regulation and it protects enzymes from radical oxygen damage [40,45]. The expression of PRDX3 is regulated by HIF1-alpha and is associated with cell proliferation and resistance to drug treatment in cancer cells [46][47][48]. In response to peroxide treatment, PRDX1 and PRDX3 forms a complex which may mediate peroxide signal transduction [49].…”

The role of peroxiredoxins in cancer

“…In medulloblastoma tumor tissue samples and cell lines, the level of the microRNA, miR-383, is a modulator of PRDX3 expression (99), whereas in human prostate cancer cells, miR-23b directly regulates PRDX3 expression under normal and hypoxic conditions (100). Finally, in von Hippel-Lindau (VHL)-deficient clear cell renal cell carcinoma (CCRCC), the transcription factor, hypoxia-inducible factor 1 (HIF-1), downregulates the level of PRDX3 (101). …”

VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2

“…Under hypoxic conditions, HIF-α is stabilized due to the inhibition of hydroxylation and ubiquitination, and it subsequently translocates into the nucleus where it forms heterodimer with constitutively expressed HIF-1β (refs 7, 8). The HIF-α/HIF-1β heterodimer binds to hypoxia-responsive elements (HREs) in the promoters and activates the transcription of its targeted genes, which are involved in energy metabolism, angiogenesis, cell proliferation/differentiation and invasion/metastasis910111213. In addition to its role in HIF regulation, VHL is also implicated in a variety of HIF-independent processes, including regulation of the extracellular matrix, microtubule stabilization and maintenance of the primary cilium, control of cell senescence, and modulation of RNA polymerase II subunits1415161718.…”