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Molecular targets for therapy

Histone deacetylase inhibitors interrupt HSP90•RASGRP1 and HSP90•CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells

Leukemia volume 31, pages 1593–1602 (2017)Cite this article

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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.

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Acknowledgements

These studies were supported by grants from the Leukemia and Lymphoma Society (6125–10), National Cancer Institute (P50 CA097274, R01 CA166741) and Predolin Foundation. We acknowledge gifts of HSP90 antibody from David Toft as well as romidepsin and 17AAG from the NCI Drug Synthesis Branch.

Author contributions

Conception and design: HD, SHK, GSN. Financial support: SHK. Collection and assembly of data: HD, KLP, CC, BK. Data analysis and interpretation: HD, CC, GSN, SHK. Manuscript writing: All authors. Final approval of manuscript: All authors.

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Author notes

  1. H Ding, K L Peterson and C Correia: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Oncology Research, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA

    H Ding, K L Peterson, C Correia, B Koh, P A Schneider & S H Kaufmann

  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA

    H Ding, C Correia & S H Kaufmann

  3. Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA

    G S Nowakowski & S H Kaufmann

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  1. H Ding
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Correspondence to S H Kaufmann.

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Ding, H., Peterson, K., Correia, C. et al. Histone deacetylase inhibitors interrupt HSP90•RASGRP1 and HSP90•CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells. Leukemia 31, 1593–1602 (2017). https://doi.org/10.1038/leu.2016.357

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