NF-Y loss triggers p53 stabilization and apoptosis in HPV18-positive cells by affecting E6 transcription

Abstract

The expression of the high risk HPV18 E6 and E7 oncogenic proteins induces the transformation of epithelial cells, through the disruption of p53 and Rb function. The binding of cellular transcription factors to cis-regulatory elements in the viral Upstream Regulatory Region (URR) stimulates E6/E7 transcription. Here, we demonstrate that the CCAAT-transcription factor NF-Y binds to a non-canonical motif within the URR and activates viral gene expression. In addition, NF-Y indirectly up-regulates HPV18 transcription through the transactivation of multiple cellular transcription factors. NF-YA depletion inhibits the expression of E6 and E7 genes and re-establishes functional p53. The activation of p53 target genes in turn leads to apoptotic cell death. Finally, we show that NF-YA loss sensitizes HPV18-positive cells toward the DNA damaging agent Doxorubicin, via p53-mediated transcriptional response.

NF-Y Subunits Overexpression in HNSCC

“…Both mechanisms were shown to impact on the NF-Y regulome: p53 mutations, specifically those with gain-of-function, directly activate several NF-Y targets [ 58 , 59 , 60 , 61 , 62 , 63 ]. As for viral proteins, NF-Y activates the E6 promoter of HPV18 in HeLa cells, via a proximal promoter CCAAT box [ 64 ]. It remains to be seen whether an increased level of NF-Y induces HPV16 E6/E7 expression.…”

“…A further issue is the co-regulation of the three subunits. In HPV18-positive HeLa cells, removal of NF-YA by RNAi leads to increased HFD levels, and, vice versa, NF-YB inactivation entails upregulation of NF-YA [ 64 ]. In HPV-positive tumors, all three subunits are upregulated: thus, the feedback loop is apparently interrupted.…”

Enhanced Susceptibility to 5-Fluorouracil in Human Colon Cancer Cells by Silencing of GRP78

“…However, the extent of 5-FU-induced cancer cell apoptosis is limited due to the developing resistance to the drug and its use is restricted because of harmful side-effects (25). In particular, it has been suggested that GRP78 counteracts the cytotoxic action of chemical therapy with 5-FU by protecting cells from 5-FU-induced apoptosis and promoting resistance to this drug (10,26). As a result, there has been an increasing interest to synergistic combination therapies, whereby multiple targets would be simultaneously affected to enhance effects of anticancer drugs.…”

Annexin A1 peptide and endothelial cell‐conditioned medium modulate cervical tumorigenesis

“…The cervical cancer apoptosis may be altered because of HPV18 infection. This virus has E6 and E7 domains, which express oncoproteins, and they are involved with p53 and retinoblastoma degradation [45][46][47]. The E6 protein, specifically, can form a complex that causes p53 polyubiquitination and its degradation by the proteasome [45,48].…”