Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming.
Despite the availability of vaccines, human papillomavirus (HPV) infections remain a cause of significant cancer morbidity and mortality. We have previously shown that HPV16 E7 associates with and diminishes E2F6-containing polycomb repressive complexes. Here, we show that repressive trimethyl marks on lysine 27 of histone 3, which are necessary for binding of polycomb repressive complexes, are decreased in HPV16 E7-expressing cells and HPV16-positive cervical lesions. This is caused by transcriptional induction of the KDM6A and KDM6B histone 3 lysine 27-specific demethylases. HPV16 E7-mediated KDM6B induction accounts for expression of the cervical cancer biomarker, p16(INK4A). Moreover, KDM6A- and KDM6B-responsive Homeobox genes are expressed at significantly higher levels, suggesting that HPV16 E7 results in reprogramming of host epithelial cells. These effects are independent of the ability of E7 to inhibit the retinoblastoma tumor suppressor protein. Most importantly, these effects are reversed when E7 expression is silenced, indicating that this pathway may have prognostic and/or therapeutic significance.
Infectious Diseases Division, Department of Medicine, The Channing Laboratory, Harvard Medical School, Boston, MA 02115, USA. mdrubin@rics.bwh.harvard.edu
Margaret E
ME
McLaughlin-Drubin
Christopher P
CP
Crum
Karl
K
Münger
D002478:Cells, Cultured; D004790:Enzyme Induction; D044127:Epigenesis, Genetic; D005260:Female; D005801:Genes, Homeobox; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis*; D050725:Papillomavirus E7 Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002583:Uterine Cervical Neoplasms / Q000821:virology
D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D056484:Jumonji Domain-Containing Histone Demethylases
Cell. 2007 Feb 23;128(4):693-705
17320507
Virus Res. 2009 Aug;143(2):195-208
19540281
Cell. 1997 Mar 7;88(5):593-602
9054499
Cancer Cell. 2010 Aug 9;18(2):135-46
20708155
Lancet. 2007 Sep 8;370(9590):890-907
17826171
Nat Rev Genet. 2007 Jan;8(1):9-22
17173055
J Virol. 2004 Apr;78(7):3533-41
15016876
Genes Dev. 2009 May 15;23(10):1177-82
19451218
Nat Rev Genet. 2006 Jan;7(1):21-33
16369569
Genes Dev. 2009 May 15;23(10):1171-6
19451217
Nucleic Acids Res. 2009 Apr;37(7):2204-10
19233876
Cell Res. 2007 Oct;17(10):850-7
17923864
J Virol. 2008 Sep;82(17):8695-705
18579589
Science. 1992 Aug 14;257(5072):971-3
1323879
Cancer Res. 2008 Dec 1;68(23):9964-72
19047178
Biochem Biophys Res Commun. 1999 Apr 21;257(3):738-45
10208853
Science. 2002 Nov 1;298(5595):1039-43
12351676
J Biol Chem. 2001 Aug 31;276(35):32844-53
11435435
J Invest Dermatol. 1993 Jul;101(1):3-8
8101208
Science. 2007 Oct 19;318(5849):447-50
17761849
Int J Cancer. 2001 Apr 15;92(2):276-84
11291057
J Virol. 2002 Sep;76(17):8710-21
12163591
Virology. 2008 Mar 1;372(1):157-64
18036631
Nature. 2007 Oct 11;449(7163):689-94
17851529
EMBO Rep. 2009 Aug;10(8):881-6
19575012
Genes Dev. 2006 May 1;20(9):1123-36
16618801
J Virol. 2006 Jul;80(13):6669-77
16775354
J Cell Biol. 1996 Dec;135(6 Pt 2):1879-87
8991098
PLoS Pathog. 2009 Feb;5(2):e1000318
19247434
Genes Dev. 2002 Nov 15;16(22):2893-905
12435631
Nat Rev Cancer. 2010 May;10(5):361-71
20357775
In Vitro Cell Dev Biol Anim. 2000 Nov-Dec;36(10):667-76
11229599
Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4350-4
8633069
Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1859-64
15684044
Carcinogenesis. 2010 Jan;31(1):27-36
19752007
Am J Pathol. 1998 Dec;153(6):1741-8
9846965
Cell. 2007 Sep 21;130(6):1083-94
17825402
Oncogene. 2003 Jun 19;22(25):3833-41
12813456
Cancer Res. 1992 Jan 1;52(1):187-93
1370074
Cell. 2002 Oct 18;111(2):185-96
12408863
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18439-44
18003914
Virology. 2002 Mar 1;294(1):47-59
11886264
Genes Dev. 2010 Feb 15;24(4):327-32
20123895
Trends Genet. 1997 May;13(5):167-70
9153995
Oncogene. 2003 Sep 11;22(39):7871-81
12970734
Cancer Res. 2003 Jan 15;63(2):476-83
12543805
EMBO J. 1999 May 4;18(9):2449-58
10228159
Genes Dev. 2008 May 1;22(9):1115-40
18451103
Curr Opin Genet Dev. 1997 Aug;7(4):488-94
9309179
Genes Dev. 2008 Jul 15;22(14):1865-70
18628393
Exp Cell Res. 2004 Feb 1;293(1):144-53
14729064