KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation.
Localized chromatin modifications of histone tails play an important role in regulating gene transcription, and aberration of these processes leads to carcinogenesis. Methylated histone lysine residues, a key player in chromatin remodeling, are demethylated by the JmjC class of enzymes. Here we show that JMJD5 (now renamed KDM8), a JmjC family member, demethylates H3K36me2 and is required for cell cycle progression. Chromatin immunoprecipitation assays applied to human genome tiling arrays in conjunction with RNA microarray revealed that KDM8 occupies the coding region of cyclin A1 and directly regulates transcription. Mechanistic analyses showed that KDM8 functioned as a transcriptional activator by inhibiting HDAC recruitment via demethylation of H3K36me2, an epigenetic repressive mark. Tumor array experiments revealed KDM8 is overexpressed in several types of cancer. In addition, loss-of-function studies in MCF7 cells leads to cell cycle arrest. These studies identified KDM8 as an important cell cycle regulator.
Hsia
Datsun A
DA
Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, University of California Davis Cancer Center, Sacramento, CA 95817, USA.
Tepper
Clifford G
CG
Pochampalli
Mamata R
MR
Hsia
Elaine Y C
EY
Izumiya
Chie
C
Huerta
Steve B
SB
Wright
Michael E
ME
Chen
Hong-Wu
HW
Kung
Hsing-Jien
HJ
Izumiya
Yoshihiro
Y
D000107:Acetylation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056750:Cyclin A1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016366:Open Reading Frames; D034622:RNA Interference; D014158:Transcription, Genetic
D056750:Cyclin A1; D006657:Histones; D056466:Histone Demethylases; C550342:KDM8 protein, human
Cell. 2007 Feb 23;128(4):707-19
17320508
Cell. 2006 May 5;125(3):467-81
16603238
J Biol Chem. 2005 May 6;280(18):17732-6
15760899
Curr Biol. 2005 May 24;15(10):942-7
15916951
Mol Cell Biol. 2005 Aug;25(16):6857-68
16055700
Nat Rev Mol Cell Biol. 2008 Mar;9(3):206-18
18292778
Mol Cell. 2005 Dec 22;20(6):971-8
16364921
EMBO J. 2006 Jul 26;25(14):3422-31
16858412
Nature. 2006 Jul 20;442(7100):312-6
16732292
Mol Cell. 2007 Jan 12;25(1):1-14
17218267
Dev Biol. 2000 Aug 15;224(2):388-400
10926775
Cell. 2007 Mar 23;128(6):1077-88
17320160
Nature. 2007 Oct 11;449(7163):731-4
17713478
Cell. 2005 Nov 18;123(4):581-92
16286007
J Biol Chem. 2007 May 25;282(21):15471-5
17409384
Nat Struct Mol Biol. 2008 Nov;15(11):1169-75
18836456
Nature. 2006 Feb 16;439(7078):811-6
16362057
Nat Genet. 2008 Jul;40(7):897-903
18552846
Science. 2007 Oct 19;318(5849):444-7
17947579
Cell. 2008 Nov 14;135(4):604-7
19013272
Cell. 2004 Dec 29;119(7):941-53
15620353
Nat Rev Genet. 2006 Sep;7(9):715-27
16983801
J Biol Chem. 2009 Mar 20;284(12):7970-6
19155214
Nat Cell Biol. 2007 Mar;9(3):347-53
17277772
Mol Cell Biol. 1999 Mar;19(3):2400-7
10022926