5-aza-2’-deoxycytidine (DAC) treatment downregulates the HPV E6 and E7 oncogene expression and blocks neoplastic growth of HPV-associated cancer cells
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Maximilian Stich1,2,*, Lennard Ganss1,2,*, Jens Puschhof1, Elena-Sophie Prigge1,2, Miriam Reuschenbach1,2, Ana Guiterrez1,2, Svetlana Vinokurova3 and Magnus von Knebel Doeberitz1,2
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Germany
2Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Institute of Carcinogenesis, NN Blokhin Cancer Research Center, Moscow, Russia
*These authors contribute equally to this work
Magnus von Knebel Doeberitz, email: [email protected]
Keywords: HPV, DNA demethylation, 5-aza-2’-deoxycytidine (DAC), miR-375, upstream regulatory region (URR)
Received: March 07, 2016 Accepted: June 03, 2016 Published: July 16, 2016
High-risk human papillomaviruses (hr HPVs) may cause various human cancers and associated premalignant lesions. Transformation of the host cells is triggered by overexpression of the viral oncogenes E6 and E7 that deregulate the cell cycle and induce chromosomal instability. This process is accompanied by hypermethylation of distinct CpG sites resulting in silencing of tumor suppressor genes, inhibition of the viral E2 mediated control of E6 and E7 transcription as well as deregulated expression of host cell microRNAs. Therefore, we hypothesized that treatment with demethylating agents might restore those regulatory mechanisms. Here we show that treatment with 5-aza-2’-deoxycytidine (DAC) strongly decreases the expression of E6 and E7 in a panel of HPV-transformed cervical cancer and head and neck squamous cell carcinoma cell lines. Reduction of E6 and E7 further resulted in increased target protein levels including p53 and p21 reducing the proliferation rates and colony formation abilities of the treated cell lines. Moreover, DAC treatment led to enhanced expression of tumor the suppressive miRNA-375 that targets and degrades E6 and E7 transcripts. Therefore, we suggest that DAC treatment of HPV-associated cancers and respective precursor lesions may constitute a targeted approach to subvert HPV oncogene functions that deserves testing in clinical trials.
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