The Histone Deacetylase Inhibitor Valproic Acid Selectively Induces Proteasomal Degradation of HDAC2

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2003 Jul 4

PMID 12840003

Citations 209

Authors

Oliver H Kramer

Ping Zhu

Heather P Ostendorff

Martin Golebiewski

Jens Tiefenbach

Marvin A Peters

Boris Brill

Bernd Groner

Ingolf Bach

Thorsten Heinzel

Martin Gottlicher

Affiliations

Soon will be listed here.

Abstract

Histone-modifying enzymes play essential roles in physiological and aberrant gene regulation. Since histone deacetylases (HDACs) are promising targets of cancer therapy, it is important to understand the mechanisms of HDAC regulation. Selective modulators of HDAC isoenzymes could serve as efficient and well-tolerated drugs. We show that HDAC2 undergoes basal turnover by the ubiquitin-proteasome pathway. Valproic acid (VPA), in addition to selectively inhibiting the catalytic activity of class I HDACs, induces proteasomal degradation of HDAC2, in contrast to other inhibitors such as trichostatin A (TSA). Basal and VPA-induced HDAC2 turnover critically depend on the E2 ubiquitin conjugase Ubc8 and the E3 ubiquitin ligase RLIM. Ubc8 gene expression is induced by both VPA and TSA, whereas only TSA simultaneously reduces RLIM protein levels and therefore fails to induce HDAC2 degradation. Thus, poly-ubiquitination and proteasomal degradation provide an isoenzyme-selective mechanism for downregulation of HDAC2.

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References

Hicke L . Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol. 2001; 2(3):195-201. DOI: 10.1038/35056583. View

Gray S, Ekstrom T . The human histone deacetylase family. Exp Cell Res. 2001; 262(2):75-83. DOI: 10.1006/excr.2000.5080. View

Kramer O, Gottlicher M, Heinzel T . Histone deacetylase as a therapeutic target. Trends Endocrinol Metab. 2001; 12(7):294-300. DOI: 10.1016/s1043-2760(01)00438-6. View

Phiel C, Zhang F, Huang E, Guenther M, Lazar M, Klein P . Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001; 276(39):36734-41. DOI: 10.1074/jbc.M101287200. View

Marks P, Richon V, Breslow R, Rifkind R . Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol. 2001; 13(6):477-83. DOI: 10.1097/00001622-200111000-00010. View

Gottlicher M, Minucci S, Zhu P, Kramer O, SCHIMPF A, Giavara S . Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001; 20(24):6969-78. PMC: 125788. DOI: 10.1093/emboj/20.24.6969. View

Ostendorff H, Peirano R, Peters M, Schluter A, Bossenz M, Scheffner M . Ubiquitination-dependent cofactor exchange on LIM homeodomain transcription factors. Nature. 2002; 416(6876):99-103. DOI: 10.1038/416099a. View

Glickman M, Ciechanover A . The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002; 82(2):373-428. DOI: 10.1152/physrev.00027.2001. View

Maurer A, Wichmann C, Gross A, Kunkel H, Heinzel T, Ruthardt M . The Stat5-RARalpha fusion protein represses transcription and differentiation through interaction with a corepressor complex. Blood. 2002; 99(8):2647-52. DOI: 10.1182/blood.v99.8.2647. View

10.

Warrell Jr R, He L, Richon V, Calleja E, Pandolfi P . Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst. 1998; 90(21):1621-5. DOI: 10.1093/jnci/90.21.1621. View

11.

Lutterbach B, Westendorf J, Linggi B, Patten A, Moniwa M, Davie J . ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol. 1998; 18(12):7176-84. PMC: 109299. DOI: 10.1128/MCB.18.12.7176. View

12.

Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci P, Lazar M . Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol. 1998; 18(12):7185-91. PMC: 109300. DOI: 10.1128/MCB.18.12.7185. View

13.

Bach I, Carriere C, Bhushan A, Krones A, Rose D, Glass C . RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex. Nat Genet. 1999; 22(4):394-9. DOI: 10.1038/11970. View

14.

Driever P, Knupfer M, Cinatl J, Wolff J . Valproic acid for the treatment of pediatric malignant glioma. Klin Padiatr. 1999; 211(4):323-8. DOI: 10.1055/s-2008-1043809. View

15.

Yang W, Yao Y, Sun J, Davie J, Seto E . Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family. J Biol Chem. 1997; 272(44):28001-7. DOI: 10.1074/jbc.272.44.28001. View

16.

Lagger G, OCarroll D, Rembold M, Khier H, Tischler J, Weitzer G . Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 2002; 21(11):2672-81. PMC: 126040. DOI: 10.1093/emboj/21.11.2672. View

17.

Kirsh O, Seeler J, Pichler A, Gast A, Muller S, Miska E . The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J. 2002; 21(11):2682-91. PMC: 125385. DOI: 10.1093/emboj/21.11.2682. View

18.

Melnick A, Licht J . Histone deacetylases as therapeutic targets in hematologic malignancies. Curr Opin Hematol. 2002; 9(4):322-32. DOI: 10.1097/00062752-200207000-00010. View

19.

David G, Neptune M, DePinho R . SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities. J Biol Chem. 2002; 277(26):23658-63. DOI: 10.1074/jbc.M203690200. View

20.

Zhang C, McKinsey T, Chang S, Antos C, Hill J, Olson E . Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell. 2002; 110(4):479-88. PMC: 4459650. DOI: 10.1016/s0092-8674(02)00861-9. View