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Heat Shock Proteins in Signaling Pathways pp 317–328Cite as

Regulation of Calcineurin Signaling Through Blocking of the Chaperone Function of Hsp90 by HDAC Inhibitors

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Part of the book series: Heat Shock Proteins ((HESP,volume 17))

Abstract

Many heat shock proteins act as molecular chaperones to regulate the stability of proteins related to cell growth and survival. Histone deacetylases (HDAC) regulate gene transcription through deacetylation of histones and are involved in cell apoptosis, senescence, differentiation, and angiogenesis. HDAC can enhance protein stability through deacetylation of Hsp90. Aberrant expression of HDAC is reported in many kinds of malignancies, so HDAC inhibitors may have utility as anti-cancer agents. Panobinostat, a pan-HDAC inhibitor, blocks Hsp90 function by inhibiting HDAC6 and shows anti-leukemic effects through degradation of CXCR4 and/or AML1-ETO protein. We found that calcineurin signaling plays an important role in the pathogenesis of multiple myeloma (MM). PPP3CA, a catalytic subunit of calcineurin, was revealed to be a target of panobinostat, which shows an anti-myeloma effect by inducing PPP3CA protein degradation through Hsp90 inhibition. The anti-myeloma effect of panobinostat was enhanced on addition of FK506 and supported the importance of PPP3CA in the pathogenesis of MM. Blocking calcineurin signaling also inhibited differentiation of osteoclasts, that is essential for lytic bone lesions frequently found in patients with MM. Thus, the usefulness of calcineurin signaling regulation by HDAC inhibitors through Hsp90 chaperone blocking was revealed.

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Abbreviations

17-AAG:

17-(allylamino)-17-demethoxygeldanamycin

AML:

acute myeloid leukemia

CsA:

cyclosporine A

CXCR4:

C-X-C-chemokine receptor type 4

ER:

estrogen receptor

GA:

geldanamycin

GEO:

gene expression omnibus

HDAC:

histone deacetylases

MAPK:

mitogen-activated protein kinase

MM:

multiple myeloma

NFATc1:

nuclear factor of activated T cells, cytoplasmic calcineurin-dependent 1

PKC:

protein kinase C

PPP3CA:

protein phosphatase 3 catalytic subunitα isozyme

RANKL:

receptor activator nuclear factor-κ-B ligand

ROS:

reactive oxygen species

SDF-1:

stromal cell-derived factor 1

T-ALL:

T cell acute lymphoblastic leukemia

Tam:

tamoxifen

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Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research of the Japan Society for the Promotion of Science, the Takeda Science Foundation, an International Myeloma Foundation Japan Grant, and the Japan Leukemia Research Fund.

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Authors and Affiliations

  1. Department of Hematology/Oncology, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yoichi Imai & Arinobu Tojo

  2. Division of Molecular Therapy, Department of The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Arinobu Tojo

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  1. Yoichi Imai
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  2. Arinobu Tojo
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Correspondence to Yoichi Imai .

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Editors and Affiliations

  1. Professor, Department of Medicine and Director, Precision Therapeutics Proteogenomics Diagnostic Center Eleanor N. Dana Cancer Center, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Punit Kaur

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Imai, Y., Tojo, A. (2019). Regulation of Calcineurin Signaling Through Blocking of the Chaperone Function of Hsp90 by HDAC Inhibitors. In: Asea, A., Kaur, P. (eds) Heat Shock Proteins in Signaling Pathways. Heat Shock Proteins, vol 17. Springer, Cham. https://doi.org/10.1007/978-3-030-03952-3_16

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