title: Histone deacetylase inhibitors interrupt HSP90•RASGRP1 and HSP90•CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells.
abstract: Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here, we show that trichostatin A, romidepsin and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen-activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo. Importantly, these pro-apoptotic effects are mimicked by RASGRP1 small interfering RNA (siRNA) or HSP90 inhibition and reversed by overexpression of constitutively active MEK1 or siRNA-mediated downregulation of BIM. Collectively, these observations not only identify a new HSP90 client protein, RASGRP1, but also delineate a complete signaling pathway from HSP90 acetylation through RASGRP1 and CRAF degradation to BIM upregulation that contributes to selective cytotoxicity of HDAC inhibitors in lymphoid malignancies.
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ding
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Correia
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Koh
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Schneider
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Nowakowski
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.|Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D019254:Genes, bcl-2; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D000072224:Bcl-2-Like Protein 11; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; C491790:RASGRP1 protein, human; D019908:Proto-Oncogene Proteins c-raf