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http://dx.doi.org/10.4062/biomolther.2020.012

SUV39H1 is a New Client Protein of Hsp90 Degradated by Chaetocin as a Novel C-Terminal Inhibitor of Hsp90  

Lian, Bin (Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China)
Lin, Qian (Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China)
Tang, Wei (Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China)
Qi, Xin (Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China)
Li, Jing (Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China)
Publication Information
Biomolecules & Therapeutics / v.29, no.1, 2021 , pp. 73-82 More about this Journal
Abstract
Hsp90 is often overexpressed with activated form in cancer cells, and many key cellular proteins are dependent upon the Hsp90 machinery (these proteins are called "client protein"). Nowadays, more client proteins and more inhibitors of Hsp90 are being discovered. Chaetocin has been identified as an inhibitor of histone methyl transferase SUV39H1. Herein, we find that Chaetocin is an inhibitor of Hsp90 which binds to the C-terminal of Hsp90α. Chaetocin inhibited a variety of Hsp90 client proteins including AMl1-ETO and BCL-ABL, the mutant fusion-protein in the K562 and HL-60 cells. SUV39H1 mediates epigenetic events in the pathophysiology of hematopoietic disorders. We found that inhibition of Hsp90 by Chaetocin and 17-AAG had ability to induce degradation of SUV39H1 through proteasome pathway. In addition, SUV39H1 interacted with Hsp90 through co-chaperone HOP. These results suggest that SUV39H1 belongs to a client protein of Hsp90. Moreover, Chaetocin was able to induce cell differentiation in the two cells in the concentration range of Hsp90 inhibition. Altogether, our results demonstrate that SUV39H1 is a new client protein of Hsp90 degradated by Chaetocin as a novel C-terminal inhibitor of Hsp90. The study establishes a new relationship of Chaetocin and SUV39H1, and paves an avenue for exploring a new strategy to target SUV39H1 by inhibition of Hsp90 in leukemia.
Keywords
Hsp90; Chaetocin; SUV39H1; Client protein; Cancer;
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1 Albacker, C. E., Storer, N. Y., Langdon, E. M., Anthony, D. B., Yi, Z., Langenau, D. M., Zhou, Y., Langenau, D. M. and Zon, L. I. (2013) The histone methyltransferase suv39h1 suppresses embryonal rhabdomyosarcoma formation in zebrafish. PLoS ONE 8, e64969-.   DOI
2 Allan, R. K., Mok, D., Ward, B. K. and Ratajczak, T. (2006) Modulation of chaperone function and cochaperone interaction by novobiocin in the c-terminal domain of Hsp90. J. Biol. Chem. 281, 7161-7171.   DOI
3 Banerji, U. (2015) O7.6 - HSP90 inhibitors in the clinic: what have we learnt? Ann. Oncol. 26, ii10.   DOI
4 Carbone, R., Botrugno, O. A., Ronzoni, S., Insinga, A., Di Croce, L., Pelicci, P. G. and Minucci, S. (2006) Recruitment of the histone methyltransferase suv39h1 and its role in the oncogenic properties of the leukemia-associated pml-retinoic acid receptor fusion protein. Mol. Cell. Biol. 26, 1288-1296.   DOI
5 Chaib, H., Nebbioso, A., Prebet, T., Castellano, R., Garbit, S., Restouin, A., Vey, N., Altucci, L. and Collette, Y. (2012) Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase suv39h1. Leukemia 26, 662-674.   DOI
6 Cherblanc, F. L., Chapman, K. L., Brown, R. and Fuchter, M. J. (2013) Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases. Nat. Chem. Biol. 9, 136-137.   DOI
7 Cherblanc, F. L., Chapman-Rothe, N., Brown, R. and Fuchter, M. (2012) Current limitations and future opportunities for epigenetic therapies. Future Med. Chem. 4, 425-446.   DOI
8 Condelli, V., Crispo, F., Pietrafesa, M., Lettini, G., Matassa, D. S., Esposito, F., Landriscina, M. and Maddalena, F. (2019) HSP90 molecular chaperones, metabolic rewiring, and epigenetics: impact on tumor progression and perspective for anticancer therapy. Cells 8, 532.   DOI
9 Copeland, R. A., Solomon, M. E. and Richon, V. M. (2009) Protein methyltransferases as a target class for drug discovery. Nat. Rev. Drug Discov. 8, 724-732.   DOI
10 Donnelly, A. and Blagg, B. S. (2008) Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Curr. Med. Chem. 15, 2702-2717.   DOI
11 Gliniewicz, E. F., Chambers, K. M., De Leon, E. R., Sibai, D., Campbell, H. C. and McMenimen, K. A. (2019) Chaperone-like activity of the N-terminal region of a human small heat shock protein and chaperone-functionalized nanoparticles. Proteins 87, 401-415.   DOI
12 Goyama, S., Nitta, E., Yoshino, T., Kako, S., Watanabe-Okochi, N., Shimabe, M., Imai, Y., Takahashi, K. and Kurokawa, M. (2010) EVI-1 interacts with histone methyltransferases suv39h1 and g9a for transcriptional repression and bone marrow immortalization. Leukemia 24, 81-88.   DOI
13 Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E. and Imhof, A. (2005) Identification of a specific inhibitor of the histone methyltransferase su(var)3-9. Nat. Chem. Biol. 1, 143-145.   DOI
14 Howes, J., Lu, B. F., Powers, M., Mitsopoulos, C., Al-Lazikani, B., Linardopoulos, S., Clarke, P. and Workman, P. (2014) Abstract 2730: RNAi knockdown or chemical inhibition of anaphase-promoting complex components is synthetic lethal with HSP90 inhibition. Cancer Res. 74, 2730.   DOI
15 Jackson, S. E. (2012) Hsp90: structure and function. Top. Curr. Chem. 328, 155-240.   DOI
16 Khandelwal, A., Crowley, V. M. and Blagg, B. S. J. (2016) Natural product inspired N-terminal Hsp90 inhibitors: from bench to bedside? Med. Res. Rev. 36, 92-118.   DOI
17 Kim, Y., Alarcon, S., Lee, S., Lee, M. J., Giaccone, G., Neckers, L. and Trepel, J. B. (2009) Update on Hsp90 inhibitors in clinical trial. Curr. Top. Med. Chem. 9, 1479-1492.   DOI
18 Yu, H., Cai, S., Gao, J., Wang, C., Qiao, X., Wang, H., Feng, L. and Wang, Y. (2016) Express sequence tag analysis - identification of anseriformes trypsin genes from full-length cDNA library of the duck (Anas platyrhynchos) and characterization of their structure and function. Biochemistry Mosc. 81, 152-162.   DOI
19 Yang, Y. J., Han, J. W., Youn, H. D. and Cho, E. J. (2010) The tumor suppressor, parafibromin, mediates histone H3 K9 methylation for cyclin D1 repression. Nucleic Acids Res. 38, 382-390.   DOI
20 Yin, X., Zhang, H., Burrows, F., Zhang, L. and Shores, C. G. (2005) Potent activity of a novel dimeric heat shock protein 90 inhibitor against head and neck squamous cell carcinoma in vitro and in vivo. Clin. Cancer Res. 11, 3889-3896.   DOI
21 Li, M., Zhang, X., Zhou, W. J., Chen, Y. H., Liu, H., Liu, L., Yang, C. M. and Qan, W. B. (2013) Hsp90 inhibitor BIIB021 enhances triptolideinduced apoptosis of human T-cell acute lymphoblastic leukemia cells in vitro mainly by disrupting p53-MDM2 balance. Acta Pharmacol. Sin. 34, 1545-1553.   DOI
22 Kumagai, T., Shih, L. Y., Hughes, S. V., Desmond, J. C., O'Kelly, J., Hewison, M. and Koeffler, H. P. (2005) 19-Nor-1,25(OH)2D2 (a novel, noncalcemic vitamin D analogue), combined with arsenic trioxide, has potent antitumor activity against myeloid leukemia. Cancer Res. 65, 2488-2497.   DOI
23 Lakshmikuttyamma, A., Scott, S. A., Decoteau, J. F. and Geyer, C. R. (2009) Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition. Oncogene 29, 576-588.   DOI
24 Li, J. and Buchner, J. (2013) Structure, function and regulation of the Hsp90 machinery. Biomed. J. 36, 106-117.   DOI
25 Li, Y., Zhang, T., Jiang, Y., Lee, H. F., Schwartz, S. J. and Sun, D. (2009) (-)-Epigallocatechin-3-gallate inhibits Hsp90 function by impairing Hsp90 association with cochaperones in pancreatic cancer cell line Mia Paca-2. Mol. Pharm. 6, 1152-1159.   DOI
26 Makhnevych, T. and Houry, W. A. (2012) The role of Hsp90 in protein complex assembly. Biochim. Biophys. Acta 1823, 674-682.   DOI
27 Mcconnell, J., Wang, Y. and Mcalpine, S. (2015) Targeting the C-terminus of Hsp90 as a cancer therapy. In Heat Shock Protein Inhibitors. Springer International Publishing.
28 Mclaughlin, S. H., Smith, H. W. and Jackson, S. E. (2002) Stimulation of the weak ATPase activity of human Hsp90 by a client protein. J. Mol. Biol. 315, 787-798.   DOI
29 Melcher, M., Schmid, M., Aagaard, L., Selenko, P., Laible, G. and Jenuwein, T. (2000) Structure-function analysis of SUV39H1 reveals a dominant role in heterochromatin organization, chromosome segregation, and mitotic progression. Mol. Cell. Biol. 20, 3728-3741.   DOI
30 Zhang, Y. M., Gao, E. E., Wang, Q. Q., Tian, H. and Hou, J. (2018) Effects of histone methyltransferase inhibitor chaetocin on histone H3K9 methylation of cultured ovine somatic cells and development of preimplantation cloned embryos. Reprod. Toxicol. 79, 124-131.   DOI
31 Mellatyar, H., Talaei, S., Pilehvar-Soltanahmadi, Y., Barzegar, A., Akbarzadeh, A., Shahabi, A., Barekati-Mowahed, M. and Zarghami, N. (2018) Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: overview and current state of the art. Biomed. Pharmacother. 102, 608-617.   DOI
32 Ochel, H. J. and Gademann, G. (2002) Heat-shock protein 90: potential involvement in the pathogenesis of malignancy and pharmacological intervention. Onkologie 25, 466-473.   DOI
33 Onuoha, S. C., Coulstock, E. T., Grossmann, J. G. and Jackson, S. E. (2008) Structural studies on the co-chaperone Hop and its complexes with Hsp90. J. Mol. Biol. 379, 732-744.   DOI
34 Orkin, S. H. and Zon, L. I. (2008) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631-644.   DOI
35 Penkler, D. L., Atilgan, C. and Tastan Bishop, O. (2018) Allosteric modulation of human hsp90α conformational dynamics. J. Chem. Inf. Model. 58, 383-404.   DOI
36 Plass, C., Oakes, C., Blum, W. and Marcucci, G. (2008) Epigenetics in acute myeloid leukemia. Semin. Oncol. 35, 378-387.   DOI
37 Rao, V. K., Pal, A. and Taneja, R. (2017) A drive in SUVs: from development to disease. Epigenetics 12, 177-186.   DOI
38 Roh, S. H., Kasembeli, M., Galaz-Montoya, J. G., Trnka, M., Lau, W. C., Burlingame, A., Chiu, W. and Tweardy, D. J. (2016) Chaperonin TRiC/CCT modulates the folding and activity of leukemogenic fusion oncoprotein AML1-ETO. J. Biol. Chem. 291, 4732-4741.   DOI
39 Rohl, A., Rohrberg, J. and Buchner, J. (2013) The chaperone Hsp90: changing partners for demanding clients. Trends Biochem. Sci. 38, 253-262.   DOI
40 Rombo, R., Weiher, H. and Schmidt-Wolf, I. G. (2016) Effect of chaetocin on renal cell carcinoma cells and cytokine-induced killer cells. Ger. Med. Sci. 14, Doc04.
41 Sahasrabudhe, P., Rohrberg, J., Biebl, M. M., Rutz, D. A. and Buchner, J. (2017) The plasticity of the Hsp90 co-chaperone system. Mol. Cell 67, 947-961.e5.   DOI
42 Saito, T., Suzuki, Y., Koyama, K., Natori, S., Iitaka, Y. and Kinosita, T. (1988) Chetracin A and chaetocins B and C, three new epipolythiodioxopiperazines from Chaetomium spp. Chem. Pharm. Bull. 36, 1942-1956.   DOI
43 Scheufler, C., Brinker, A., Bourenkov, G., Pegoraro, S., Moroder, L., Bartunik, H., Hartl, F. U. and Moarefi, I. (2000) Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell 101, 199-210.   DOI
44 Song, X., Zhao, Z., Qi, X., Tang, S., Wang, Q., Zhu, T., Gu, Q., Liu, M. and Li, J. (2015) Identification of epipolythiodioxopiperazines HDN1 and chaetocin as novel inhibitor of heat shock protein 90. Oncotarget 6, 5263-5274.   DOI
45 Taipale, M., Krykbaeva, I., Koeva, M., Kayatekin, C., Westover, K., Karras, G. I. and Lindquist, S. (2012) Quantitative analysis of Hsp90-client interactions reveals principles of substrate recognition. Cell 150, 987-1001.   DOI
46 Theodoraki, M. A., Kunjappu, M., Sternberg, D. W. and Caplan, A. J. (2007) Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context. Exp. Cell Res. 313, 3851-3858.   DOI
47 Xu, W., Yuan, X., Xiang, Z., Mimnaugh, E., Marcu, M. and Neckers, L. (2005) Surface charge and hydrophobicity determine ErbB2 binding to the Hsp90 chaperone complex. Nat. Struct. Mol. Biol. 12, 120-126.   DOI
48 Wang, Y., Fiskus, W., Natarajan, K., Yang, Y., Rao, R., Chen, J., Joshi, A., Koul, S., Upadhyay, S., Balusu, R., Fernandez, P., Buckley, K., Jillella, A., Quadt, C., Atadja, P., Levine, R. and Bhalla, K. (2009) Abstract #3722: co-treatment with pan-HDAC inhibitor panobinostat or heat shock protein (hsp) 90 inhibitor AUY922 with JAK2 inhibitor TG101209 is highly active against bone marrow progenitor cells from myeloproliferative neoplasms (MPN). Cancer Res. 69, 3722.