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Molecular and Cellular Biology, December 2009, p. 6149-6169, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.01481-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-xL, and Mcl-1{triangledown}

Shuang Chen,1,{dagger} Yun Dai,1,{dagger} Xin-Yan Pei,1 and Steven Grant1,2,3,4*

Department of Medicine,1 Department of Biochemistry,2 Massey Cancer Center,3 Institute for Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 232984

Received 22 September 2008/ Returned for modification 28 December 2008/ Accepted 21 September 2009

The Bcl-2 antagonist ABT-737 kills transformed cells in association with displacement of Bim from Bcl-2. The histone deactetylase (HDAC) inhibitor suberoyl bis-hydroxamic acid (SBHA) was employed to determine whether and by what mechanism ABT-737 might interact with agents that upregulate Bim. Expression profiling of BH3-only proteins indicated that SBHA increased Bim, Puma, and Noxa expression, while SBHA concentrations that upregulated Bim significantly potentiated ABT-737 lethality. Concordance between SBHA-mediated Bim upregulation and interactions with ABT-737 was observed in various human leukemia and myeloma cells. SBHA-induced Bim was largely sequestered by Bcl-2 and Bcl-xL, rather than Mcl-1; ABT-737 attenuated these interactions, thereby triggering Bak/Bax activation and mitochondrial outer membrane permeabilization. Knockdown of Bim (but not Puma or Noxa) by shRNA or ectopic overexpression of Bcl-2, Bcl-xL, or Mcl-1 diminished Bax/Bak activation and apoptosis. Notably, ectopic expression of these antiapoptotic proteins disabled death signaling by sequestering different proapoptotic proteins, i.e., Bim by Bcl-2, both Bim and Bak by Bcl-xL, and Bak by Mcl-1. Together, these findings indicate that HDAC inhibitor-inducible Bim is primarily neutralized by Bcl-2 and Bcl-xL, thus providing a mechanistic framework by which Bcl-2 antagonists potentiate the lethality of agents, such as HDAC inhibitors, which upregulate Bim.

* Corresponding author. Mailing address: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Massey Cancer Center, Goodwin Research Building, Room 234, 401 College Street, Richmond, VA 23298. Phone: (804) 828-5211. Fax: (804) 828-2178. E-mail: stgrant{at}vcu.edu

{triangledown} Published ahead of print on 5 October 2009.

{dagger} S.C. and Y.D. contributed equally to this work.

Molecular and Cellular Biology, December 2009, p. 6149-6169, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.01481-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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