COMMD1 disrupts HIF-1alpha/beta dimerization and inhibits human tumor cell invasion.
The gene encoding COMM domain-containing 1 (COMMD1) is a prototypical member of the COMMD gene family that has been shown to inhibit both NF-kappaB- and HIF-mediated gene expression. NF-kappaB and HIF are transcription factors that have been shown to play a role in promoting tumor growth, survival, and invasion. In this study, we demonstrate that COMMD1 expression is frequently suppressed in human cancer and that decreased COMMD1 expression correlates with a more invasive tumor phenotype. We found that direct repression of COMMD1 in human cell lines led to increased tumor invasion in a chick xenograft model, while increased COMMD1 expression in mouse melanoma cells led to decreased lung metastasis in a mouse model. Decreased COMMD1 expression also correlated with increased expression of genes known to promote cancer cell invasiveness, including direct targets of HIF. Mechanistically, our studies show that COMMD1 inhibits HIF-mediated gene expression by binding directly to the amino terminus of HIF-1alpha, preventing its dimerization with HIF-1beta and subsequent DNA binding and transcriptional activation. Altogether, our findings demonstrate a role for COMMD1 in tumor invasion and provide a detailed mechanism of how this factor regulates the HIF pathway in cancer cells.
van de Sluis
Bart
B
Complex Genetics Section, Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
Mao
Xicheng
X
Zhai
Yali
Y
Groot
Arjan J
AJ
Vermeulen
Jeroen F
JF
van der Wall
Elsken
E
van Diest
Paul J
PJ
Hofker
Marten H
MH
Wijmenga
Cisca
C
Klomp
Leo W
LW
Cho
Kathleen R
KR
Fearon
Eric R
ER
Vooijs
Marc
M
Burstein
Ezra
E
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics; D055503:Protein Multimerization; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C480519:COMMD1 protein, human; D002352:Carrier Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014157:Transcription Factors
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7987-92
9653127
Oncogene. 2008 Mar 6;27(11):1501-10
17873906
Cell. 2003 Jan 24;112(2):169-80
12553906
Curr Opin Genet Dev. 2007 Feb;17(1):71-7
17208433
Nature. 2003 Sep 18;425(6955):307-11
13679920
Kidney Int. 2005 Aug;68(2):569-83
16014034
Nature. 2003 Dec 18;426(6968):853-7
14685242
J Cell Physiol. 2005 Jul;204(1):146-54
15672417
EMBO J. 2004 Jan 14;23(1):244-54
14685266
J Biol Chem. 2003 Jun 13;278(24):21631-8
12690099
Nature. 1999 May 20;399(6733):271-5
10353251
J Clin Invest. 2007 Dec;117(12):3810-20
18037992
J Clin Invest. 2004 Aug;114(4):569-81
15314694
FASEB J. 2004 Jun;18(9):1028-30
15084514
Cancer Cell. 2009 Jun 2;15(6):527-38
19477431
Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
7539918
Cell Mol Life Sci. 2007 Aug;64(15):1997-2005
17497243
Cancer Cell. 2009 Jan 6;15(1):35-44
19111879
Hum Mol Genet. 2002 Jan 15;11(2):165-73
11809725
Mol Cell Biol. 2007 Jun;27(11):4142-56
17371845
Nature. 2008 Jun 5;453(7196):807-11
18432192
Nat Med. 2008 May;14(5):518-27
18438415
Curr Mol Med. 2008 Feb;8(1):60-7
18289014
J Hepatol. 2003 Nov;39(5):703-9
14568250
J Biol Chem. 2005 Jun 10;280(23):22222-32
15799966
Mol Cell. 2007 Jan 26;25(2):207-17
17244529
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):811-6
14711987
J Cell Biochem. 2008 Jun 1;104(3):733-44
18253935
Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9309-14
15184677
EMBO J. 2007 Jan 24;26(2):436-47
17183367
Cancer Cell. 2003 Apr;3(4):347-61
12726861
Science. 2001 Nov 9;294(5545):1337-40
11598268
Curr Opin Cell Biol. 2005 Oct;17(5):548-58
16098727
Nature. 2006 Apr 27;440(7088):1222-6
16642001
Curr Opin Genet Dev. 2008 Feb;18(1):19-26
18440219
J Biol Chem. 2002 Aug 16;277(33):29936-44
12052835
Oncogene. 2007 Feb 1;26(5):711-24
16862183
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18154-9
17114296
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13350-5
14595015
J Biol Chem. 2000 Oct 13;275(41):32234-43
10918053
Cancer Res. 2006 Jan 15;66(2):820-7
16424014
Traffic. 2009 May;10(5):514-27
19220812
Biochem J. 2009 Jan 15;417(2):601-9
18795889
Lab Invest. 2006 Apr;86(4):345-56
16482104
J Soc Gynecol Investig. 2004 Jan;11(1):51-9
14706684
PLoS One. 2009 Oct 05;4(10):e7332
19802386
Nat Cell Biol. 2008 Mar;10(3):295-305
18297062
Oncogene. 2005 Oct 6;24(44):6626-36
16103885