Oncotarget

Research Papers:

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

Paolo Benatti _, Valentina Basile, Diletta Dolfini, Silvia Belluti, Margherita Tomei and Carol Imbriano

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Oncotarget. 2016; 7:45901-45915. https://doi.org/10.18632/oncotarget.9974

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Abstract

Paolo Benatti1,*, Valentina Basile1,*, Diletta Dolfini2, Silvia Belluti1, Margherita Tomei1, Carol Imbriano1

1Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, 41125 Modena, Italy

2Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy

*These authors have contributed equally to this work

Correspondence to:

Carol Imbriano, email: cimbriano@unimo.it

Keywords: NF-Y, CCAAT-box, HPV18, p53, gene transcription

Abbreviations: Human Papilloma Virus, HPV; Transcription Factor, TF; Long Control Region, LCR; Upstream Regulatory Region, URR

Received: November 10, 2015    Accepted: June 01, 2016    Published: June 13, 2016

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.


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