Histone demethylase KDM3A is required for enhancer activation of hippo target genes in colorectal cancer.
Adaptor Proteins, Signal Transducing
/ genetics
Carcinogenesis
/ genetics
Cell Line, Tumor
Colorectal Neoplasms
/ genetics
DNA-Binding Proteins
/ genetics
Enhancer Elements, Genetic
/ genetics
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Hippo Signaling Pathway
Histone-Lysine N-Methyltransferase
/ genetics
Humans
Jumonji Domain-Containing Histone Demethylases
/ genetics
Nuclear Proteins
/ genetics
Phosphoproteins
/ genetics
Prognosis
Promoter Regions, Genetic
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Signal Transduction
TEA Domain Transcription Factors
Transcription Factors
/ genetics
YAP-Signaling Proteins
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
18 03 2019
18 03 2019
Historique:
accepted:
08
01
2019
revised:
18
12
2018
received:
19
11
2018
pubmed:
17
1
2019
medline:
16
10
2019
entrez:
17
1
2019
Statut:
ppublish
Résumé
Hippo pathway is involved in tumorigenesis, and its regulation in cytosol has been extensively studied, but its regulatory mechanisms in the nuclear are not clear. In the current study, using a FBS-inducing model following serum starvation, we identified KDM3A, a demethylase of histone H3K9me1/2, as a positive regulator for hippo target genes. KDM3A promotes gene expression through two mechanisms, one is to upregulate YAP1 expression, and the other is to facilitate H3K27ac on the enhancers of hippo target genes. H3K27ac upregulation is more relevant with gene activation, but not H3K4me3; and KDM3A depletion caused H3K9me2 upregulation mainly on TEAD1-binding enhancers rather than gene bodies, further resulting in H3K27ac decrease, less TEAD1 binding on enhancers and impaired transcription. Moreover, KDM3A is associated with p300 and required for p300 recruitment to enhancers. KDM3A deficiency delayed cancer cell growth and migration, which was rescued by YAP1 expression. KDM3A expression is correlated with YAP1 and hippo target genes in colorectal cancer patient tissues, and may serve as a potential prognosis mark. Taken together, our study reveals novel mechanisms for hippo signaling and enhancer activation, which is critical for tumorigenesis of colorectal cancer.
Identifiants
pubmed: 30649550
pii: 5289487
doi: 10.1093/nar/gky1317
pmc: PMC6412006
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
DNA-Binding Proteins
0
Nuclear Proteins
0
Phosphoproteins
0
TEA Domain Transcription Factors
0
TEAD1 protein, human
0
Transcription Factors
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
KDM3A protein, human
EC 1.14.11.-
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2349-2364Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Cell. 2013 Aug 1;154(3):541-55
pubmed: 23871696
Epigenomics. 2017 Sep;9(9):1219-1231
pubmed: 28799793
Cell. 2008 Nov 14;135(4):604-7
pubmed: 19013272
Mol Cancer Res. 2016 Nov;14(11):1033-1044
pubmed: 27555595
J Med Chem. 2011 Sep 8;54(17):6139-50
pubmed: 21780790
Cancer Cell. 2016 Jun 13;29(6):783-803
pubmed: 27300434
Nature. 2007 Nov 1;450(7166):119-23
pubmed: 17943087
Acta Biochim Biophys Sin (Shanghai). 2012 Jan;44(1):70-9
pubmed: 22194015
PLoS One. 2015 Jan 06;10(1):e0116782
pubmed: 25562686
Nat Cell Biol. 2015 May;17(5):615-626
pubmed: 25915126
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Nucleic Acids Res. 2015 Jan;43(1):196-207
pubmed: 25488809
Cell Res. 2014 Mar;24(3):331-43
pubmed: 24458094
Am J Cancer Res. 2012;2(5):478-91
pubmed: 22957302
Mol Cell Biol. 2013 Dec;33(23):4745-54
pubmed: 24081332
Cell. 2006 May 5;125(3):483-95
pubmed: 16603237
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
PLoS Biol. 2014 Dec 23;12(12):e1002026
pubmed: 25535969
Mol Cell. 2013 Mar 7;49(5):825-37
pubmed: 23473601
Nat Commun. 2017 Jan 04;8:14058
pubmed: 28051067
Nat Genet. 2015 Jan;47(1):8-12
pubmed: 25547603
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11871-11876
pubmed: 27698142
Nat Cell Biol. 2017 Apr;19(4):362-374
pubmed: 28346439
Cell. 2013 Nov 7;155(4):934-47
pubmed: 24119843
Cancer Res. 2017 May 1;77(9):2413-2423
pubmed: 28249901
Nat Rev Genet. 2014 Apr;15(4):272-86
pubmed: 24614317
Genes Dev. 2012 Dec 1;26(23):2604-20
pubmed: 23166019
Genes Dev. 2011 Apr 15;25(8):781-8
pubmed: 21498567
Trends Cell Biol. 2015 Sep;25(9):499-513
pubmed: 26045258
Cancer Res. 2017 Dec 1;77(23):6614-6626
pubmed: 28951465
Nucleic Acids Res. 2017 Jan 9;45(1):92-105
pubmed: 27614073
Annu Rev Biochem. 2006;75:243-69
pubmed: 16756492
Oncogene. 2008 Dec;27 Suppl 1:S71-83
pubmed: 19641508
Cell. 2015 Jan 29;160(3):554-66
pubmed: 25635462
Genes Dev. 2008 Jul 15;22(14):1962-71
pubmed: 18579750
Mol Cell Biol. 2010 Jan;30(1):344-53
pubmed: 19858293
Cell. 2015 Nov 5;163(4):811-28
pubmed: 26544935
Clin Epigenetics. 2016 Mar 31;8:34
pubmed: 27034728
Curr Biol. 2010 Sep 14;20(17):1580-7
pubmed: 20727758
Cell. 2017 Aug 24;170(5):875-888.e20
pubmed: 28757253
Nat Rev Genet. 2010 Nov;11(11):749
pubmed: 20921960
Dig Dis Sci. 2017 Dec;62(12):3460-3467
pubmed: 29094309
Genes Dev. 2016 Jan 1;30(1):1-17
pubmed: 26728553
Biochim Biophys Acta. 2012 Dec;1826(2):357-64
pubmed: 22683405
Cancer Res. 2017 Dec 1;77(23):6489-6498
pubmed: 29097609
Nat Commun. 2016 Feb 12;7:10574
pubmed: 26868148
Dev Cell. 2013 May 28;25(4):388-401
pubmed: 23725764
Cell Death Differ. 2019 Jun;26(6):1156-1168
pubmed: 30237511