SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis
Open accessAbstract
Mutant p53 (mutp53) cancers are surprisingly dependent on their hyperstable mutp53 protein for survival, identifying mutp53 as a potentially significant clinical target. However, exploration of effective small molecule therapies targeting mutp53 has barely begun. Mutp53 hyperstabilization, a hallmark of p53 mutation, is cancer cell-specific and due to massive upregulation of the HSP90 chaperone machinery during malignant transformation. We recently showed that stable complex formation between HSP90 and its mutp53 client inhibits E3 ligases MDM2 and CHIP, causing mutp53 stabilization. Histone deacetylase (HDAC) inhibitors (HDACi) are a new class of promising anti-cancer drugs, hyperacetylating histone and non-histone targets. Currently, suberoylanilide hydroxamic acid (SAHA) is the only FDA-approved HDACi. We show that SAHA exhibits preferential cytotoxicity for mutant, rather than wild-type and null p53 human cancer cells. Loss/gain-of-function experiments revealed that although able to exert multiple cellular effects, SAHA's cytotoxicity is caused to a significant degree by its ability to strongly destabilize mutp53 at the level of protein degradation. The underlying mechanism is SAHA's inhibition of HDAC6, an essential positive regulator of HSP90. This releases mutp53 and enables its MDM2- and CHIP-mediated degradation. SAHA also strongly chemosensitizes mutp53 cancer cells for chemotherapy due to its ability to degrade mutp53. This identifies a novel action of SAHA with the prospect of SAHA becoming a centerpiece in mutp53-specific anticancer strategies.
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HDAC inhibitor SAHA shows strong effects in destabilizing mut-p53 by dissociating HDAC6 from functional interaction with Hsp90 and thereby inhibits glioblastoma growth and resistance to chemotherapy.
“HDAC inhibitor SAHA shows strong effects in destabilizing mut-p53 by dissociating HDAC6 from functional interaction with Hsp90 and thereby inhibits GBM growth and resistance to chemotherapy [142,143,144,145,146].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [142]
The Results and Discussion report that SAHA inhibits HDAC6, disrupts Hsp90’s interaction with mutant p53, and sensitizes mutant-p53 cancer cells to chemotherapy. They do not report dissociation of HDAC6 from Hsp90. The Methods list breast, colon, prostate, pancreatic, and ovarian mutant-p53 cell lines, not glioblastoma cells, so the claimed effect on GBM growth and chemotherapy resistance is not established by this paper. (LLM, conf=0.90)
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Cites
Anticancer activities of histone deacetylase inhibitors
Bolden, J. E., Peart, M. J., & Johnstone, R. W. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2133 · Cited by 2,919 · see citing works
HSP90 and the chaperoning of cancer
Whitesell, L., & Lindquist, S. L. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1716 · Cited by 2,502 · see citing works
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer
Minucci, S., & Pelicci, P. G. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1779 · Cited by 2,211 · see citing works
Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome
Olive, K. P., Tuveson, D. A., Ruhe, Z. C., Yin, B., Willis, N. A., Bronson, R. T., Crowley, D., & Jacks, T. (2004) · Cell · doi:10.1016/j.cell.2004.11.004 · Cited by 1,308 · see citing works
HDAC6 Regulates Hsp90 Acetylation and Chaperone-Dependent Activation of Glucocorticoid Receptor
Kovacs, J. J., Murphy, P. J. M., Gaillard, S., Zhao, X., Wu, J.-T., Nicchitta, C. V., Yoshida, M., Toft, D. O., Pratt, W. B., & Yao, T.-P. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.021 · Cited by 1,153 · see citing works
Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome
Lang, G. A., Iwakuma, T., Suh, Y.-A., Liu, G., Rao, V. A., Parant, J. M., Valentin-Vega, Y. A., Terzian, T., Caldwell, L. C., Strong, L. C., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.006 · Cited by 1,069 · see citing works
Mutant p53 drives invasion by promoting integrin recycling
Muller, P. A. J., Caswell, P. T., Doyle, B., Iwanicki, M. P., Tan, E. H., Karim, S., Lukashchuk, N., Gillespie, D. A., Ludwig, R. L., Gosselin, P., et al. (2009) · Cell · doi:10.1016/j.cell.2009.11.026 · Cited by 796 · see citing works
A Mutant-p53/Smad Complex Opposes p63 to Empower TGFβ-Induced Metastasis
Adorno, M., Cordenonsi, M., Montagner, M., Dupont, S., Wong, C., Hann, B. C., Solari, A., Bobisse, S., Rondina, M. B., Guzzardo, V., et al. (2009) · Cell · doi:10.1016/j.cell.2009.01.039 · Cited by 783 · see citing works
Gui, C., Ngo, L., Xu, W., Richon, V. M., & Marks, P. A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307708100 · Cited by 550 · see citing works
p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug
Wang, S.-P., Wang, W.-L., Chang, Y.-L., Wu, C.-T., Chao, Y.-C., Kao, S.-H., Yuan, A., Lin, C.-W., Yang, S.-C., Chan, W.-K., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1875 · Cited by 493 · see citing works
Carew, J. S., Nawrocki, S. T., Kahue, C. N., Zhang, H., Yang, C., Chung, L., Houghton, J. A., Huang, P., Giles, F. J., & Cleveland, J. L. (2007) · Blood · doi:10.1182/blood-2006-10-050260 · Cited by 487 · see citing works
Blandino, G., Levine, A. J., & Oren, M. (1999) · Oncogene · doi:10.1038/sj.onc.1202314 · Cited by 439 · see citing works
An Acetylation Site in the Middle Domain of Hsp90 Regulates Chaperone Function
Scroggins, B. T., Robzyk, K., Wang, D., Marcu, M. G., Tsutsumi, S., Beebe, K., Cotter, R. J., Felts, S., Toft, D., Karnitz, L., et al. (2007) · Molecular Cell · doi:10.1016/j.molcel.2006.12.008 · Cited by 413 · see citing works
Chemosensitivity linked to p73 function
Irwin, M. S., Kondo, K., Marín, M. C., Cheng, L. S., Hahn, W. C., & Kaelin, W. G. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00078-3 · Cited by 406 · see citing works
The role of mutant p53 in human cancer
Goh, A. M., Coffill, C. R., & Lane, D. P. (2010) · The Journal of Pathology · doi:10.1002/path.2784 · Cited by 398 · see citing works
Modulation of p53, ErbB1, ErbB2, and Raf-1 Expression in Lung Cancer Cells by Depsipeptide FR901228
Yu, X. (2002) · CancerSpectrum Knowledge Environment · doi:10.1093/jnci/94.7.504 · Cited by 360 · see citing works
The inherent instability of mutant p53 is alleviated by Mdm2 or p16 INK4a lossPreprint
Terzian, T., Suh, Y., Iwakuma, T., Post, S. M., Neumann, M., Lang, G. A., Pelt, C. S. V., & Lozano, G. (2008) · Genes & Development · doi:10.1101/gad.1662908 · Cited by 356 · see citing works
Li, D., Marchenko, N. D., Schulz‐Heddergott, R., Fischer, V., Velasco-Hernández, T., Talos, F., & Moll, U. M. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-10-0534 · Cited by 298 · see citing works
Self-citationNimmanapalli, R., Fuino, L., Bali, P., Gasparetto, M., Glozak, M. A., Tao, J., Moscinski, L. C., Smith, C. A., Wu, J., Jove, R., et al. (2003) · PubMed · Cited by 276 · see citing works
Fuino, L., Bali, P., Wittmann, S., Donapaty, S., Guo, F., Yamaguchi, H., Wang, H., Atadja, P. W., & Bhalla, K. N. (2003) · PubMed · Cited by 261 · see citing works
The Chaperone-associated Ubiquitin Ligase CHIP Is Able to Target p53 for Proteasomal Degradation
Esser, C., Scheffner, M., & Höhfeld, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501574200 · Cited by 260 · see citing works
Tsutsumi, S., & Neckers, L. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00561.x · Cited by 239 · see citing works
Ubiquitination and Degradation of Mutant p53
Lukashchuk, N., & Vousden, K. H. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00050-07 · Cited by 223 · see citing works
Whitesell, L. J., Sutphin, P. D., Pulcini, E. J., Martinez, J. D., & Cook, P. H. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.3.1517 · Cited by 207 · see citing works
Bossi, G., Lapi, E., Strano, S., Rinaldo, C., Blandino, G., & Sacchi, A. (2005) · Oncogene · doi:10.1038/sj.onc.1209026 · Cited by 202 · see citing works
Lindemann, R. K., Newbold, A., Whitecross, K. F., Cluse, L. A., Frew, A. J., Ellis, L., Williams, S. P., Wiegmans, A. P., Dear, A. E., Scott, C. L., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702294104 · Cited by 199 · see citing works
Gibbs, A., Schwartzman, J. A., Deng, V., & Alumkal, J. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908908106 · Cited by 174 · see citing works
King, F. W., Wawrzynów, A., Höhfeld, J., & Żylicz, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.22.6297 · Cited by 167 · see citing works
Mutant p53 protein expression interferes with p53-independent apoptotic pathways
Li, R., Sutphin, P. D., Schwartz, D., Matas, D., Almog, N., Wolkowicz, R., Goldfinger, N., Pei, H., Prokocimer, M., & Rotter, V. (1998) · Oncogene · doi:10.1038/sj.onc.1201867 · Cited by 140 · see citing works
Bali, P., George, P., Cohen, P. S., Tao, J., Guo, F., Sigua, C. A., Vishvanath, A., Scuto, A., Annavarapu, S., Fiskus, W. C., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0210 · Cited by 127 · see citing works
Geldanamycin-stimulated destabilization of mutated p53 is mediated by the proteasome in vivo
Whitesell, L. J., Sutphin, P. D., An, W. G., Schulte, T. W., Blagosklonny, M. V., & Neckers, L. (1997) · Oncogene · doi:10.1038/sj.onc.1201120 · Cited by 127 · see citing works
Beyer, U., Moll-Rocek, J., Moll, U. M., & Dobbelstein, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016201108 · Cited by 113 · see citing works
Self-citationMühlenberg, T., Zhang, Y., Wagner, A. J., Grabellus, F., Bradner, J. E., Taeger, G., Lang, H., Taguchi, T., Schüler, M., Fletcher, J. A., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4004 · Cited by 90 · see citing works
Depletion of Mutant p53 and Cytotoxicity of Histone Deacetylase Inhibitors
Blagosklonny, M. V., Trostel, S. Y., Kayastha, G., Demidenko, Z. N., Vassilev, L. T., Romanova, L. Y., Bates, S. E., & Fojo, T. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3433 · Cited by 83 · see citing works
Varshochi, R., Halim, F., Sunters, A., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408063200 · Cited by 73 · see citing works
Yan, W., Liu, G., Scoumanne, A., & Chen, X. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0810 · Cited by 64 · see citing works
Yi, X., Wei, W., Wang, S., Du, Z., Xu, Y.-J., & Yu, X. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.10.035 · Cited by 51 · see citing works
Induction of TAp63 by histone deacetylase inhibitors
Sayan, B. S., Yang, A. L., Conforti, F., Bernardini, S., Tucci, P., Vasa‐Nicotera, M., Knight, R. A., & Melino, G. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.12.147 · Cited by 9 · see citing works
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Muller, P. A. J., & Vousden, K. H. (2013) · Nature Cell Biology · doi:10.1038/ncb2641 · Cited by 1,647 · see citing works
Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others
Sabapathy, K., & Lane, D. P. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.151 · Cited by 517 · see citing works
The p53 Pathway in Glioblastoma
Zhang, Y., Dube, C., Gibert, M., Cruickshanks, N., Wang, B., Coughlan, M., Yang, Y., Setiady, I., Deveau, C., Saoud, K., et al. (2018) · Cancers · doi:10.3390/cancers10090297 · Cited by 440 · see citing works
Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy
Yue, X., Zhao, Y., Xu, Y., Zheng, M., Feng, Z., & Hu, W. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.03.030 · Cited by 308 · see citing works
Walerych, D., Lisek, K., Sommaggio, R., Piazza, S., Ciani, Y., Dalla, E., Rajkowska, K., Gaweda-Walerych, K., Ingallina, E., Tonelli, C., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3380 · Cited by 239 · see citing works
Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8
Yan, W., Liu, S., Xu, E., Zhang, J., Zhang, Y., Chen, X., & Chen, X. (2013) · Oncogene · doi:10.1038/onc.2012.81 · Cited by 153 · see citing works
Hu, H.-F., Ye, Z., Qin, Y., Xu, X.-W., Yu, X.-J., Zhuo, Q.-F., & Ji, S.-R. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00584-2 · Cited by 149 · see citing works
Xia, C., Tao, Y., Li, M., Che, T., & Qu, J. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.9073 · Cited by 136 · see citing works
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Nishikawa, S., & Iwakuma, T. (2023) · Cancers · doi:10.3390/cancers15020429 · Cited by 115 · see citing works
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Hunter, A. M., & Sallman, D. A. (2019) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2019.05.004 · Cited by 102 · see citing works
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Levine, A. J. (2019) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055455 · Cited by 84 · see citing works
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Ryu, H.-W., Shin, D.-H., Lee, D. H., Choi, J., Han, G., Lee, K. Y., & Kwon, S. H. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.01.033 · Cited by 82 · see citing works
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Niazi, S., Purohit, M., & Niazi, J. H. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.08.099 · Cited by 65 · see citing works
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Yang, X.-F., Zhao, Z.-J., Liu, J.-J., Yang, X.-H., Gao, Y., Zhao, S., Shi, S., Huang, K.-Q., & Zheng, H.-C. (2017) · Oncotarget · doi:10.18632/oncotarget.13680 · Cited by 15 · see citing works
- Authors
- Li, D., Marchenko, N. D., & Moll, U. M.
- Affiliations
- Stony Brook University (US)
- Corresponding author
- Marchenko, N D
- Moll, U M
- Venue
- Cell Death & Differentiation
- Published
- 2011-06-03
- Volume
- 18
- Issue
- 12
- Pages
- 1904-1913
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3170683
- OpenAlex
- W2075676198
- Cited by
- 336
- References
- 38
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 17 · 2023: 17 · 2022: 24 · 2021: 36 · 2020: 23 · 2019: 31 · 2018: 29 · 2017: 26 · 2016: 30 · 2015: 28 · 2014: 14 · 2013: 16 · 2012: 15
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- Stony Brook University
- National Cancer Institute (R01CA060664, CA0664, R01CA093853, CA93853)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- mutant p53, vorinostat, HDAC6, HSP90, protein stabilization, MDM2, CHIP, E3 ubiquitin ligase, protein degradation, histone deacetylase inhibitors, chemosensitization
- MeSH terms
- Histone Deacetylase 6, Vorinostat, Antineoplastic Agents, Cell Movement, Cell Survival, Clinical Trials as Topic, Enzyme Activation, Histone Deacetylases, Humans, Hydroxamic Acids, Leupeptins, Down-Regulation, Tumor Suppressor Protein p53, HSP90 Heat-Shock Proteins, Inhibitory Concentration 50, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proteasome Endopeptidase Complex, Mutant Proteins, Proto-Oncogene Proteins c-mdm2, Protein Stability, Histone Deacetylase Inhibitors, Molecular Targeted Therapy, Proteolysis, Proteasome Inhibitors
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