Microarray-based transcriptional and epigenetic profiling of matrix metalloproteinases, collagens, and related genes in cancer.
Epigenetic parameters (DNA methylation, histone modifications, and miRNAs) play a significant role in cancer. To identify the common epigenetic signatures of both the individual matrix metalloproteinases (MMPs) and the additional genes, the function of which is also linked to proteolysis, migration, and tumorigenesis, we performed epigenetic profiling of 486 selected genes in unrelated non-migratory MCF-7 breast carcinoma and highly migratory U251 glioma cells. Genome-wide transcriptional profiling, quantitative reverse transcription-PCR, and microRNA analyses were used to support the results of our epigenetic studies. Transcriptional silencing in both glioma and breast carcinoma cells predominantly involved the repressive histone H3 Lys-27 trimethylation (H3K27me3) mark. In turn, epigenetic stimulation was primarily performed through a gain in the histone H3 Lys-4 dimethylation (H3K4me2) and H3 hyperacetylation and by a global reduction of H3K27me3. Inactive pro-invasive genes in MCF-7 cells but not in U251 cells frequently exhibited a stem cell-like bivalent mark (enrichment in both H3K27me3 and H3K4me2), a characteristic of developmental genes. In contrast with other MMPs, MMP-8 was epigenetically silenced in both cell types, thus providing evidence for the strict epigenetic control of this anti-tumorigenic proteinase in cancer. Epigenetic stimulation of multiple collagen genes observed in cultured glioma cells was then directly confirmed using orthotopic xenografts and tumor specimens. We suggest that the epigenetic mechanisms allow gliomas to deposit an invasion-promoting collagen-enriched matrix and then to use this matrix to accomplish their rapid migration through the brain tissue.
Chernov
Andrei V
AV
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Baranovskaya
Svetlana
S
Golubkov
Vladislav S
VS
Wakeman
Dustin R
DR
Snyder
Evan Y
EY
Williams
Roy
R
Strongin
Alex Y
AY
D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation; D019281:Dimerization; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis
D020782:Matrix Metalloproteinases
Nat Genet. 2006 May;38(5):500-1
16642009
Nature. 2001 Mar 1;410(6824):120-4
11242054
Biochem Biophys Res Commun. 2009 Aug 14;386(1):1-5
19523920
Cell. 2007 May 18;129(4):823-37
17512414
Nat Struct Mol Biol. 2005 Feb;12(2):110-2
15702071
J Biol Chem. 2009 May 8;284(19):12727-34
19286653
Cancer Lett. 2008 Dec 18;272(2):197-205
19013014
Cell. 2007 Oct 5;131(1):29-32
17923085
J Biol Chem. 2000 Dec 15;275(50):39237-45
11007770
Cell. 2007 Feb 23;128(4):693-705
17320507
J Cell Physiol. 2004 Jul;200(1):11-9
15137053
Lab Invest. 2010 Feb;90(2):144-55
20048743
Nat Rev Genet. 2002 Jun;3(6):415-28
12042769
Curr Opin Struct Biol. 2005 Feb;15(1):107-15
15718141
J Biol Chem. 2006 Sep 8;281(36):26196-204
16849317
Methods Mol Biol. 2000;132:365-86
10547847
Curr Biol. 2001 Mar 6;11(5):R185-97
11267889
Brain Res. 2010 Feb 2;1312:120-6
19948152
Nature. 2001 Mar 1;410(6824):116-20
11242053
IUBMB Life. 2006 Oct;58(10):589-96
17050376
Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3542-52
19387070
J Biol Chem. 2009 Oct 23;284(43):29893-904
19625257
Hum Mol Genet. 2009 Oct 1;18(19):3594-604
19584087
Science. 2001 Apr 6;292(5514):110-3
11283354
Science. 2008 Sep 26;321(5897):1807-12
18772396
Arthritis Rheum. 2005 Oct;52(10):3110-24
16200590
Clin Cancer Res. 2006 Dec 1;12(23):7009-17
17145822
Expert Rev Anticancer Ther. 2009 Nov;9(11):1663-74
19895249
Nat Cell Biol. 2006 May;8(5):532-8
16570078
Biochem Biophys Res Commun. 2002 Oct 4;297(4):765-72
12359218
J Cell Sci. 2009 Nov 15;122(Pt 22):4042-8
19861500
BMC Med. 2008 Jun 24;6:14
18577219
Front Biosci. 2007 Jan 01;12:528-35
17127314
Biol Chem. 1997 Mar-Apr;378(3-4):151-60
9165065
Cell. 2006 Apr 21;125(2):315-26
16630819
PLoS One. 2010 Mar 22;5(3):e9808
20339555
Nat Genet. 2009 May;41(5):518-20
19330028
Cell Stem Cell. 2007 Sep 13;1(3):286-98
18371363
Nat Rev Mol Cell Biol. 2002 Oct;3(10):753-66
12360192
Oncogene. 2007 Apr 19;26(18):2563-73
17099729
Circ Res. 2003 May 2;92(8):827-39
12730128
Genes Dev. 2001 Sep 15;15(18):2343-60
11562345
Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15782-7
17043231
Cancer Metastasis Rev. 2008 Jun;27(2):289-302
18286233
Int J Oncol. 2009 Jun;34(6):1653-60
19424584
Nat Genet. 2008 May;40(5):499-507
18443585
Genomics. 1992 Jul;13(3):881-3
1639418
Int J Oncol. 2010 Apr;36(4):913-20
20198336
Cancer Res. 2008 Sep 15;68(18):7247-9
18794108
Nat Rev Cancer. 2002 Mar;2(3):161-74
11990853
Annu Rev Med. 2009;60:167-79
19630570
Nat Rev Genet. 2009 Oct;10(10):704-14
19763153
J Biol Chem. 2001 Mar 9;276(10):6983-92
11114293
J Biol Chem. 2008 May 30;283(22):14910-4
18411277
Nat Genet. 2002 Jan;30(1):77-80
11740497
Oncogene. 2007 Aug 9;26(36):5229-37
17325663
Cancer Res. 2008 Apr 15;68(8):2755-63
18413742
Cancer Res. 2002 Jan 15;62(2):580-8
11809713
Cell. 2004 Jan 23;116(2):281-97
14744438
Cancer Cell. 2006 Apr;9(4):287-300
16616334
J Immunol. 2008 Apr 1;180(7):5036-44
18354229