Functional Interplay Between Histone Demethylase and Deacetylase Enzymes

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2006 Aug 18

PMID 16914725

Citations 119

Authors

Min Gyu Lee

Christopher Wynder

Daniel A Bochar

Mohamed-Ali Hakimi

Neil Cooch

Ramin Shiekhattar

Affiliations

Soon will be listed here.

Abstract

Histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents for the treatment of solid and hematological malignancies. The precise mechanism by which HDAC inhibitors mediate their effects on tumor cell growth, differentiation, and/or apoptosis is the subject of intense research. Previously we described a family of multiprotein complexes that contain histone deacetylase 1/2 (HDAC1/2) and the histone demethylase BHC110 (LSD1). Here we show that HDAC inhibitors diminish histone H3 lysine 4 (H3K4) demethylation by BHC110 in vitro. In vivo analysis revealed an increased H3K4 methylation concomitant with inhibition of nucleosomal deacetylation by HDAC inhibitors. Reconstitution of recombinant complexes revealed a functional connection between HDAC1 and BHC110 only when nucleosomal substrates were used. Importantly, while the enzymatic activity of BHC110 is required to achieve optimal deacetylation in vitro, in vivo analysis following ectopic expression of an enzymatically dead mutant of BHC110 (K661A) confirmed the functional cross talk between the demethylase and deacetylase enzymes. Our studies not only reveal an intimate link between the histone demethylase and deacetylase enzymes but also identify histone demethylation as a secondary target of HDAC inhibitors.

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References

Shi Y, Matson C, Lan F, Iwase S, Baba T, Shi Y . Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell. 2005; 19(6):857-64. DOI: 10.1016/j.molcel.2005.08.027. View

Utley R, Juan L, Cote J, Adams C, Workman J . In vitro analysis of transcription factor binding to nucleosomes and nucleosome disruption/displacement. Methods Enzymol. 1996; 274:276-91. DOI: 10.1016/s0076-6879(96)74024-7. View

Tsukada Y, Fang J, Erdjument-Bromage H, Warren M, Borchers C, Tempst P . Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2005; 439(7078):811-6. DOI: 10.1038/nature04433. View

Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J . JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell. 2006; 125(3):483-95. DOI: 10.1016/j.cell.2006.03.027. View

Whetstine J, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z . Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell. 2006; 125(3):467-81. DOI: 10.1016/j.cell.2006.03.028. View

Humphrey G, Wang Y, Russanova V, Hirai T, Qin J, Nakatani Y . Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J Biol Chem. 2000; 276(9):6817-24. DOI: 10.1074/jbc.M007372200. View

Jenuwein T, Allis C . Translating the histone code. Science. 2001; 293(5532):1074-80. DOI: 10.1126/science.1063127. View

Lo W, Duggan L, Emre N, Belotserkovskya R, Lane W, Shiekhattar R . Snf1--a histone kinase that works in concert with the histone acetyltransferase Gcn5 to regulate transcription. Science. 2001; 293(5532):1142-6. DOI: 10.1126/science.1062322. View

Guenther M, Barak O, Lazar M . The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol Cell Biol. 2001; 21(18):6091-101. PMC: 87326. DOI: 10.1128/MCB.21.18.6091-6101.2001. View

10.

Ballas N, Battaglioli E, Atouf F, Andres M, Chenoweth J, Anderson M . Regulation of neuronal traits by a novel transcriptional complex. Neuron. 2001; 31(3):353-65. DOI: 10.1016/s0896-6273(01)00371-3. View

11.

Hakimi M, Bochar D, Chenoweth J, Lane W, Mandel G, Shiekhattar R . A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci U S A. 2002; 99(11):7420-5. PMC: 124246. DOI: 10.1073/pnas.112008599. View

12.

Sun Z, Allis C . Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature. 2002; 418(6893):104-8. DOI: 10.1038/nature00883. View

13.

Dover J, Schneider J, Tawiah-Boateng M, Wood A, Dean K, Johnston M . Methylation of histone H3 by COMPASS requires ubiquitination of histone H2B by Rad6. J Biol Chem. 2002; 277(32):28368-71. DOI: 10.1074/jbc.C200348200. View

14.

Ng H, Xu R, Zhang Y, Struhl K . Ubiquitination of histone H2B by Rad6 is required for efficient Dot1-mediated methylation of histone H3 lysine 79. J Biol Chem. 2002; 277(38):34655-7. DOI: 10.1074/jbc.C200433200. View

15.

Jarriault S, Greenwald I . Suppressors of the egg-laying defective phenotype of sel-12 presenilin mutants implicate the CoREST corepressor complex in LIN-12/Notch signaling in C. elegans. Genes Dev. 2002; 16(20):2713-28. PMC: 187465. DOI: 10.1101/gad.1022402. View

16.

Eimer S, Lakowski B, Donhauser R, Baumeister R . Loss of spr-5 bypasses the requirement for the C.elegans presenilin sel-12 by derepressing hop-1. EMBO J. 2002; 21(21):5787-96. PMC: 131058. DOI: 10.1093/emboj/cdf561. View

17.

Ding Z, Gillespie L, Paterno G . Human MI-ER1 alpha and beta function as transcriptional repressors by recruitment of histone deacetylase 1 to their conserved ELM2 domain. Mol Cell Biol. 2002; 23(1):250-8. PMC: 140656. DOI: 10.1128/MCB.23.1.250-258.2003. View

18.

Hakimi M, Dong Y, Lane W, Speicher D, Shiekhattar R . A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J Biol Chem. 2002; 278(9):7234-9. DOI: 10.1074/jbc.M208992200. View

19.

Shi Y, Sawada J, Sui G, Affar E, Whetstine J, Lan F . Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003; 422(6933):735-8. DOI: 10.1038/nature01550. View

20.

Vaquero A, Loyola A, Reinberg D . The constantly changing face of chromatin. Sci Aging Knowledge Environ. 2003; 2003(14):RE4. DOI: 10.1126/sageke.2003.14.re4. View