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

Abstract

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.

Candidate gene expression patterns in rabbit preimplantation embryos developed in vivo and in vitro

“…The lower acetylation levels reported from ZGA till blastocyst, when HDAC1 reaches peak expression implies a requirement for HDAC1 to tide over ZGA. The requirement of BCLXL for ZGA was also evident from the expression pattern observed [51]. The lower levels of HDAC1 under in vitro condition may indicate a comparatively poor reprogramming of genome.…”

“…It was demonstrated that, when the expression of HDAC1 is inhibited, expression of BCLXL goes down and results in apoptosis [51]. Studies conducted on mouse preimplantation embryos have also demonstrated the crucial role of BCLXL in protecting the embryos to enter ZGA phase [28,29].…”

“…Studies on human cancer cell lines have provided evidence for the regulation of BCL2 and BCLXL by HDAC1 [51]. It was demonstrated that, when the expression of HDAC1 is inhibited, expression of BCLXL goes down and results in apoptosis [51].…”

Current and Emerging Therapies in T-cell Acute Lymphoblastic Leukemia

“…147,148 Potently, its binding activity disrupts the interactions of these pro-survival proteins with their pro-apoptotic counterparts, leading to activation of BH3-only proteins including BIM and BID, which in turn sensitize cells to or trigger apoptosis. This mechanism involves an increase in cleaved fragments of PARP, and caspase-8 and cytochrome C levels shortly after treatment with ABT-737 at low micromolar concentrations.…”

ABT-737 accelerates butyrate-induced death of HL-60 cells. Involvement of mitochondrial apoptosis pathway

“…It seems that the extent of Bcl-2 bound to Bim, rather than total Bcl-2 expression levels, may determine cellular sensitivity to ABT-737 (Deng et al 2007). In hand with this, ABT-737 has been shown to interact with certain anticancer agents capable of up-regulating BIM, (Kuroda et al 2006;Zhang et al 2008) including histone deacetylase inhibitors (HDACi) (Chen et al 2009). However, ABT-737 could synergize with HDACi in vitro to kill lymphoma cells over-expressing Bcl-2 and Bcl-X L (Whitecross et al 2009).…”