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

  • Yoichi ImaiEmail author
  • Arinobu Tojo
Chapter
Part of the Heat Shock Proteins book series (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.

Keywords

Bortezomib Calcineurin HDAC inhibitor Hsp90 Multiple myeloma Panobinostat 

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

Notes

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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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Hematology/Oncology, IMSUT Hospital, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  2. 2.Division of Molecular Therapy, Department of The Advanced Clinical Research Center, The Institute of Medical ScienceThe University of TokyoTokyoJapan

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