PMID- 28881717
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20170925
LR  - 20181113
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 32
DP  - 2017 Aug 8
TI  - 5-aza-2'-deoxycytidine (DAC) treatment downregulates the HPV E6 and E7 oncogene 
      expression and blocks neoplastic growth of HPV-associated cancer cells.
PG  - 52104-52117
LID - 10.18632/oncotarget.10631 [doi]
AB  - 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.
FAU - Stich, Maximilian
AU  - Stich M
AD  - Department of Applied Tumor Biology, Institute of Pathology, University of 
      Heidelberg, Germany.
AD  - Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
FAU - Ganss, Lennard
AU  - Ganss L
AD  - Department of Applied Tumor Biology, Institute of Pathology, University of 
      Heidelberg, Germany.
AD  - Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
FAU - Puschhof, Jens
AU  - Puschhof J
AD  - Department of Applied Tumor Biology, Institute of Pathology, University of 
      Heidelberg, Germany.
FAU - Prigge, Elena-Sophie
AU  - Prigge ES
AD  - Department of Applied Tumor Biology, Institute of Pathology, University of 
      Heidelberg, Germany.
AD  - Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
FAU - Reuschenbach, Miriam
AU  - Reuschenbach M
AD  - Department of Applied Tumor Biology, Institute of Pathology, University of 
      Heidelberg, Germany.
AD  - Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
FAU - Guiterrez, Ana
AU  - Guiterrez A
AD  - Department of Applied Tumor Biology, Institute of Pathology, University of 
      Heidelberg, Germany.
AD  - Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
FAU - Vinokurova, Svetlana
AU  - Vinokurova S
AD  - Institute of Carcinogenesis, NN Blokhin Cancer Research Center, Moscow, Russia.
FAU - von Knebel Doeberitz, Magnus
AU  - von Knebel Doeberitz M
AD  - Department of Applied Tumor Biology, Institute of Pathology, University of 
      Heidelberg, Germany.
AD  - Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
LA  - eng
PT  - Journal Article
DEP - 20160716
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5581016
OTO - NOTNLM
OT  - 5-aza-2'-deoxycytidine (DAC)
OT  - DNA demethylation
OT  - HPV
OT  - miR-375
OT  - upstream regulatory region (URR)
COIS- CONFLICTS OF INTEREST Svetlana Vinokurova and Magnus von Knebel Doeberitz are 
      listed as inventors in a patent application of the University Hospital Heidelberg 
      that is related to the research presented in this paper. The other authors 
      declare that they have no competing interests.
EDAT- 2016/07/16 00:00
MHDA- 2016/07/16 00:01
PMCR- 2017/08/08
CRDT- 2017/09/09 06:00
PHST- 2016/03/07 00:00 [received]
PHST- 2016/06/03 00:00 [accepted]
PHST- 2017/09/09 06:00 [entrez]
PHST- 2016/07/16 00:00 [pubmed]
PHST- 2016/07/16 00:01 [medline]
PHST- 2017/08/08 00:00 [pmc-release]
AID - 10631 [pii]
AID - 10.18632/oncotarget.10631 [doi]
PST - epublish
SO  - Oncotarget. 2016 Jul 16;8(32):52104-52117. doi: 10.18632/oncotarget.10631. 
      eCollection 2017 Aug 8.