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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- 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
References
Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T, Kido S, Oshima T, Shibata H, Ozaki S, Inoue D, Matsumoto T (2004) Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood 104:2484–2491
Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4:349–360
Agnelli L, Bicciato S, Mattioli M, Fabris S, Intini D, Verdelli D, Baldini L, Morabito F, Callea V, Lombardi L, Neri A (2005) Molecular classification of multiple myeloma: a distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations. J Clin Oncol 23:7296–7306
Beliakoff J, Bagatell R, Paine-Murrieta G, Taylor CW, Lykkesfeldt AE, Whitesell L (2003) Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors. Clin Cancer Res 9:4961–4971
Bhattacharyya S, Deb J, Patra AK, Thuy Pham DA, Chen W, Vaeth M, Berberich-Siebelt F, Klein-Hessling S, Lamperti ED, Reifenberg K, Jellusova J, Schweizer A, Nitschke L, Leich E, Rosenwald A, Brunner C, Engelmann S, Bommhardt U, Avots A, Müller MR, Kondo E, Serfling E (2011) NFATc1 affects mouse splenic B cell function by controlling the calcineurin-NFAT signaling network. J Exp Med 208:823–839
Bots M, Verbrugge I, Martin BP, Salmon JM, Ghisi M, Baker A, Stanley K, Shortt J, Ossenkoppele GJ, Zuber J, Rappaport AR, Atadja P, Lowe SW, Johnstone RW (2014) Differentiation therapy for the treatment of t(8;21) acute myeloid leukemia using histone deacetylase inhibitors. Blood 123:1341–1352
Boyault C, Sadoul K, Pabion M, Khochbin S (2007) HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene 26:5468–5476
Brewin J, Mancao C, Straathof K, Karlsson H, Samarasinghe S, Amrolia PJ, Pule M (2009) Generation of EBV-specific cytotoxic T cells that are resistant to calcineurin inhibitors for the treatment of posttransplantation lymphoproliferative disease. Blood 114:4792–4803
Carrasco DR, Tonon G, Huang Y, Zhang Y, Sinha R, Feng B, Stewart JP, Zhan F, Khatry D, Protopopova M, Protopopov A, Sukhdeo K, Hanamura I, Stephens O, Barlogie B, Anderson KC, Chin L, Shaughnessy JD, Brennan C, Depinho RA (2006) High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 9:313–325
Cheng J, Tang W, Su Z, Wei Q (2011) Mutation of calcineurin subunit B M118 influences the activities of NF-AT and p53, but not calcineurin expression level. Biochem Biophys Res Commun 413:481–486
Durie BG, Salmon SE (1975) A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 36:842–854
Duvic M, Dimopoulos M (2016) The safety profile of vorinostat (suberoylanilide hydroxamic acid) in hematologic malignancies: a review of clinical studies. Cancer Treat Rev 43:58–66
Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Pérez-Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400
Fu L, Lin-Lee YC, Pham LV, Tamayo A, Yoshimura L, Ford RJ (2006) Constitutive NF-kB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas. Blood 107:4540–4548
Gachet S, Ghysdael J (2009) Calcineurin/NFAT signaling in lymphoid malignancies. Gen Physiol Biophys 28:F47–F54
García-Mata R, Bebök Z, Sorscher EJ, Sztul ES (1999) Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera. J Cell Biol 146:1239–1254
Gartel AL (2007) P21(WAF1/CIP1) may be a tumor suppressor after all. Cancer Biol Ther 6:1171–1172
Glozak MA, Seto E (2007) Histone deacetylases and cancer. Oncogene 26:5420–5432
Gui CY, Ngo L, Xu WS, Richon VM, Marks PA (2004) Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A 101:1241–1246
Hemenway CS, Heitman J (1999) Calcineurin. Structure, function, and inhibition. Cell Biochem Biophys 30:115–151
Hideshima T, Richardson PG, Anderson KC (2011) Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther 10:2034–2042
Holt SE, Aisner DL, Baur J, Tesmer VM, Dy M, Ouellette M, Trager JB, Morin GB, Toft DO, Shay JW, Wright WE, White MA (1999) Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev 13:817–826
Imai Y, Maru Y, Tanaka J (2016a) Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies. Cancer Sci 107:1543–1549
Imai Y, Ohta E, Takeda S, Sunamura S, Ishibashi M, Tamura H, Wang YH, Deguchi A, Tanaka J, Maru Y, Motoji T (2016b) Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma. JCI Insight 1:e85061
Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143:1883–1898
Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M, Braggio E, Henry T, Zhu YX, Fogle H, Price-Troska T, Ahmann G, Mancini C, Brents LA, Kumar S, Greipp P, Dispenzieri A, Bryant B, Mulligan G, Bruhn L, Barrett M, Valdez R, Trent J, Stewart AK, Carpten J, Bergsagel PL (2007) Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 12:131–144
Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530
LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, Neuberg D, Goloubeva O, Pien CS, Adams J, Gupta D, Richardson PG, Munshi NC, Anderson KC (2002) Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 62:4996–5000
Mandawat A, Fiskus W, Buckley KM, Robbins K, Rao R, Balusu R, Navenot JM, Wang ZX, Ustun C, Chong DG, Atadja P, Fujii N, Peiper SC, Bhalla K (2010) Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists. Blood 116:5306–5315
Medyouf H, Alcalde H, Berthier C, Guillemin MC, dos Santos NR, Janin A, Decaudin D, de Thé H, Ghysdael J (2007) Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nat Med 13:736–741
Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G, Schlossman R, Chauhan D, Munshi NC, Hideshima T, Richon VM, Marks PA, Anderson KC (2003) Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101:4055–4062
Müller AM, Duque J, Shizuru JA, Lübbert M (2008) Complementing mutations in core binding factor leukemias: from mouse models to clinical applications. Oncogene 27:5759–5773
Münster PN, Marchion DC, Basso AD, Rosen N (2002) Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3′-kinase-AKT-dependent pathway. Cancer Res 62:3132–3137
Neilson JR, Winslow MM, Hur EM, Crabtree GR (2004) Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity 20:255–266
Noborio-Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M, Nobuyoshi M, Oh I, Sato K, Suzuki T, Ozaki K, Mori M, Nagai T, Muroi K, Kano Y, Furukawa Y, Ozawa K (2009) Bortezomib overcomes cell-adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene 28:231–242
Ocio EM, Vilanova D, Atadja P, Maiso P, Crusoe E, Fernández-Lázaro D, Garayoa M, San-Segundo L, Hernández-Iglesias T, de Alava E, Shao W, Yao YM, Pandiella A, San-Miguel JF (2010) In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica 95:794–803
Ozdağ H, Teschendorff AE, Ahmed AA, Hyland SJ, Blenkiron C, Bobrow L, Veerakumarasivam A, Burtt G, Subkhankulova T, Arends MJ, Collins VP, Bowtell D, Kouzarides T, Brenton JD, Caldas C (2006) Differential expression of selected histone modifier genes in human solid cancers. BMC Genomics 7:90
Pei XY, Dai Y, Grant S (2004) Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 10:3839–3852
Pham LV, Tamayo AT, Yoshimura LC, Lin-Lee YC, Ford RJ (2005) Constitutive NF-kappaB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival. Blood 106:3940–3947
Plemper RK, Wolf DH (1999) Retrograde protein translocation: ERADication of secretory proteins in health and disease. Trends Biochem Sci 24:266–270
Pratt WB (1998) The hsp90-based chaperone system: involvement in signal transduction from a variety of hormone and growth factor receptors. Proc Soc Exp Biol Med 217:420–434
Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH (1997) Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90:65–75
Rao A, Luo C, Hogan PG (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15:707–747
Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, Mukhopadhyay S, Ondovik MS, Khan M, Paley CS, Lonial S (2013) PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 122:2331–2337
Sadoul K, Khochbin S (2016) The growing landscape of tubulin acetylation: lysine 40 and many more. Biochem J 473:1859–1868
Schulte TW, Blagosklonny MV, Romanova L, Mushinski JF, Monia BP, Johnston JF, Nguyen P, Trepel J, Neckers LM (1996) Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. Mol Cell Biol 16:5839–5845
Spange S, Wagner T, Heinzel T, Krämer OH (2009) Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol 41:185–198
Spoo AC, Lübbert M, Wierda WG, Burger JA (2007) CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood 109:786–791
Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP (1997) Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89:239–250
Stepanova L, Leng X, Parker SB, Harper JW (1996) Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev 10:1491–1502
Trushin SA, Pennington KN, Algeciras-Schimnich A, Paya CV (1999) Protein kinase C and calcineurin synergize to activate IkappaB kinase and NF-kappaB in T lymphocytes. J Biol Chem 274:22923–22931
West AC, Johnstone RW (2014) New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 124:30–39
Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772
Zawawi MS, Dharmapatni AA, Cantley MD, McHugh KP, Haynes DR, Crotti TN (2012) Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation. Biochem Biophys Res Commun 427:404–409
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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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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