SMAR1 binds to T(C/G) repeat and inhibits tumor progression by regulating miR-371-373 cluster.
Chromatin architecture and dynamics are regulated by various histone and non-histone proteins. The matrix attachment region binding proteins (MARBPs) play a central role in chromatin organization and function through numerous regulatory proteins. In the present study, we demonstrate that nuclear matrix protein SMAR1 orchestrates global gene regulation as determined by massively parallel ChIP-sequencing. The study revealed that SMAR1 binds to T(C/G) repeat and targets genes involved in diverse biological pathways. We observe that SMAR1 binds and targets distinctly different genes based on the availability of p53. Our data suggest that SMAR1 binds and regulates one of the imperative microRNA clusters in cancer and metastasis, miR-371-373. It negatively regulates miR-371-373 transcription as confirmed by SMAR1 overexpression and knockdown studies. Further, deletion studies indicate that a ~200 bp region in the miR-371-373 promoter is necessary for SMAR1 binding and transcriptional repression. Recruitment of HDAC1/mSin3A complex by SMAR1, concomitant with alteration of histone marks results in downregulation of the miRNA cluster. The regulation of miR-371-373 by SMAR1 inhibits breast cancer tumorigenesis and metastasis as determined by in vivo experiments. Overall, our study highlights the binding of SMAR1 to T(C/G) repeat and its role in cancer through miR-371-373.
Chromatin and Disease Biology Lab, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411007, India.
Jinumary
J
Mathai
Department of Zoology, Savitribai Phule Pune University Campus, Pune 411007, India.
Smriti P K
SP
Mittal
Chromatin and Disease Biology Lab, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411007, India.
Aftab
A
Alam
Chromatin and Disease Biology Lab, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411007, India.
Payal
P
Ranade
Chromatin and Disease Biology Lab, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411007, India.
Devraj
D
Mogare
Chromatin and Disease Biology Lab, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411007, India.
Sonal
S
Patel
Bioinformatics Centre, Savitribai Phule Pune University Campus, Pune 411007, India.
Smita
S
Saxena
Chromatin and Disease Biology Lab, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411007, India.
Suvankar
S
Ghorai
Bioinformatics Centre, Savitribai Phule Pune University Campus, Pune 411007, India.
Abhijeet P
AP
Kulkarni
Chromatin and Disease Biology Lab, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411007, India.
Samit
S
Chattopadhyay
Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15819-24
19721002
Cell. 2006 Mar 24;124(6):1169-81
16564011
Mol Cell Biol. 1999 Feb;19(2):1279-88
9891062
Nature. 1979 Dec 13;282(5740):680-6
514347
Nat Methods. 2012 Mar 04;9(4):357-9
22388286
J Biol Chem. 2012 Aug 31;287(36):30641-52
22825848
Gene. 2009 Dec 1;448(1):88-101
19733223
Carcinogenesis. 2001 Feb;22(2):295-300
11181451
Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):E3374-83
26080397
Nucleic Acids Res. 2011 Jul;39(Web Server issue):W323-7
21609949
J Biol Chem. 2005 Apr 22;280(16):16019-29
15701641
Mol Oncol. 2012 Dec;6(6):590-610
23102669
Stem Cells Dev. 2010 Jul;19(7):935-50
20128659
Genome Res. 2002 Jun;12(6):996-1006
12045153
Cell Death Dis. 2010 Nov 04;1:e94
21368870
FEBS J. 2011 Jun;278(12):2044-54
21481188
Oncogene. 2012 Jun 14;31(24):2968-78
22020335
Mol Cell Biol. 2011 Jan;31(1):203-14
21041476
BMC Bioinformatics. 2010 Aug 06;11:415
20691053
BMC Bioinformatics. 2011 Dec 15;12:474
22172014
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15557-62
16230613
Oncogene. 2012 Jan 5;31(1):80-92
21643017
Bioinformatics. 2009 Aug 15;25(16):2078-9
19505943
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1608-13
18227514
Mol Cell. 2010 May 28;38(4):576-89
20513432
Nature. 2005 Jun 9;435(7043):745-6
15944682
Nucleic Acids Res. 1990 May 25;18(10):3077-8
2349120
Nucleic Acids Res. 2009 Jul;37(Web Server issue):W202-8
19458158
Nat Cell Biol. 2008 Feb;10(2):202-10
18193036
Nature. 1981 Dec 3;294(5840):417-22
6796893
Genome Biol. 2008;9(9):R137
18798982
Mol Cell Biol. 2005 Oct;25(19):8415-29
16166625
EMBO J. 2010 Feb 17;29(4):830-42
20075864
Nat Genet. 1992 Apr;1(1):45-9
1301998
Int J Biochem Cell Biol. 2013 Nov;45(11):2519-29
23876508
Cell Death Differ. 2013 Feb;20(2):367
23175189
Int J Biochem Cell Biol. 2009 Apr;41(4):862-71
18822384
Exp Cell Res. 2009 Sep 10;315(15):2529-38
19501585
PLoS One. 2013 Dec 18;8(12):e82241
24367507
PLoS One. 2014 Jul 09;9(7):e102117
25007265
Nat Biotechnol. 2011 Jan;29(1):24-6
21221095
PLoS One. 2007 Aug 01;2(7):e660
17668048
Mol Genet Genomics. 2008 Apr;279(4):429-39
18236078
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14753-8
9405685
Mol Cancer. 2013 Apr 23;12:30
23617834
PLoS One. 2014 Nov 20;9(11):e112930
25411783
Int J Biochem Cell Biol. 2012 Jan;44(1):46-52
22074660
Science. 2001 Oct 26;294(5543):853-8
11679670
Oncotarget. 2015 Jun 20;6(17 ):15180-93
25893382
Int J Clin Exp Pathol. 2009;2(4):361-9
19158933
Nat Protoc. 2009;4(1):44-57
19131956
EMBO J. 2002 Aug 1;21(15):4081-93
12145208
Oncol Rep. 2011 Nov;26(5):1329-35
21785829
PLoS Genet. 2006 Mar;2(3):e26
16520826
Nat Commun. 2013;4:2724
24201333
Mol Biol Rep. 2010 Oct;37(7):3553-60
20174991
PLoS Genet. 2014 Feb 27;10(2):e1004177
24586203
J Virol. 2000 Mar;74(6):2489-501
10684263
PLoS Comput Biol. 2007 Mar 23;3(3):e39
17381235
Development. 2005 Nov;132(21):4653-62
16224045