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Inhibition of histone deacetylase 2 reduces MDM2 expression and reduces tumor growth in dedifferentiated liposarcoma

Dedifferentiated liposarcoma (DDLPS) is a highly morbid mesenchymal tumor characterized and driven by genomic amplification of the MDM2 gene. Direct inhibition of MDM2 has shown promise pre-clinically, but has yet to be validated in clinical trials. Early in vitro studies have demonstrated that pan-...

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Autores principales: Seligson, Nathan D., Stets, Colin W., Demoret, Bryce W., Awasthi, Achal, Grosenbacher, Nicholas, Shakya, Reena, Hays, John L., Chen, James L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779286/
https://www.ncbi.nlm.nih.gov/pubmed/31620242
http://dx.doi.org/10.18632/oncotarget.27144
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author Seligson, Nathan D.
Stets, Colin W.
Demoret, Bryce W.
Awasthi, Achal
Grosenbacher, Nicholas
Shakya, Reena
Hays, John L.
Chen, James L.
author_facet Seligson, Nathan D.
Stets, Colin W.
Demoret, Bryce W.
Awasthi, Achal
Grosenbacher, Nicholas
Shakya, Reena
Hays, John L.
Chen, James L.
author_sort Seligson, Nathan D.
collection PubMed
description Dedifferentiated liposarcoma (DDLPS) is a highly morbid mesenchymal tumor characterized and driven by genomic amplification of the MDM2 gene. Direct inhibition of MDM2 has shown promise pre-clinically, but has yet to be validated in clinical trials. Early in vitro studies have demonstrated that pan-histone deacetylase (HDAC) inhibition may have anti-MDM2 effects. Here we present in silico, in vitro, and mouse xenograft studies that suggest that specifically targeting HDAC2 reduces MDM2 expression and has anti-tumor affects in DDLPS. Two independent datasets, The Cancer Genome Atlas (TCGA; n = 58) and the Memorial Sloan-Kettering Cancer Center Dataset (MSKCC; n = 63), were used to identify the co-expression between class I HDACs and MDM2, and their clinical impact. HDAC2 was highly co-expressed with MDM2 (TCGA: Spearman’s coefficient = 0.29, p = 0.03; MSKCC: Spearman’s coefficient = 0.57, p < 0.001). As both a continuous and dichotomous predictor, elevated HDAC2 expression was associated with worsened disease-free survival in the TCGA (Continuous: Hazard-ratio (HR) 1.7; 95% Confidence Interval (95%CI) 0.97–2.9; p = 0.06; Dichotomous: HR 7.1, 95%CI 2.5–19.8, p < 0.001) and distant recurrence-free survival in the MSKCC (Continuous: HR 2.2; 95%CI 1.1–4.8; p = 0.04; Dichotomous: HR 2.8, 95%CI 1.2–6.4, p = 0.02). In vitro, treatment of DDLPS cell lines with the HDAC inhibitors MI-192 (HDAC2/3 inhibitor) or romidepsin (HDAC1/2 inhibitor) reduced MDM2 expression and induced apoptosis. In a murine DDLPS xenograft model, romidepsin reduced tumor growth and lowered tumor MDM2 expression. RNA-sequencing of romidepsin treated mouse tumors demonstrated markers of TP53 reactivation. Taken together, our data supports the hypothesis that targeting HDAC2 may represent a potential strategy to modulate MDM2 expression in DDLPS.
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spelling pubmed-67792862019-10-16 Inhibition of histone deacetylase 2 reduces MDM2 expression and reduces tumor growth in dedifferentiated liposarcoma Seligson, Nathan D. Stets, Colin W. Demoret, Bryce W. Awasthi, Achal Grosenbacher, Nicholas Shakya, Reena Hays, John L. Chen, James L. Oncotarget Research Paper Dedifferentiated liposarcoma (DDLPS) is a highly morbid mesenchymal tumor characterized and driven by genomic amplification of the MDM2 gene. Direct inhibition of MDM2 has shown promise pre-clinically, but has yet to be validated in clinical trials. Early in vitro studies have demonstrated that pan-histone deacetylase (HDAC) inhibition may have anti-MDM2 effects. Here we present in silico, in vitro, and mouse xenograft studies that suggest that specifically targeting HDAC2 reduces MDM2 expression and has anti-tumor affects in DDLPS. Two independent datasets, The Cancer Genome Atlas (TCGA; n = 58) and the Memorial Sloan-Kettering Cancer Center Dataset (MSKCC; n = 63), were used to identify the co-expression between class I HDACs and MDM2, and their clinical impact. HDAC2 was highly co-expressed with MDM2 (TCGA: Spearman’s coefficient = 0.29, p = 0.03; MSKCC: Spearman’s coefficient = 0.57, p < 0.001). As both a continuous and dichotomous predictor, elevated HDAC2 expression was associated with worsened disease-free survival in the TCGA (Continuous: Hazard-ratio (HR) 1.7; 95% Confidence Interval (95%CI) 0.97–2.9; p = 0.06; Dichotomous: HR 7.1, 95%CI 2.5–19.8, p < 0.001) and distant recurrence-free survival in the MSKCC (Continuous: HR 2.2; 95%CI 1.1–4.8; p = 0.04; Dichotomous: HR 2.8, 95%CI 1.2–6.4, p = 0.02). In vitro, treatment of DDLPS cell lines with the HDAC inhibitors MI-192 (HDAC2/3 inhibitor) or romidepsin (HDAC1/2 inhibitor) reduced MDM2 expression and induced apoptosis. In a murine DDLPS xenograft model, romidepsin reduced tumor growth and lowered tumor MDM2 expression. RNA-sequencing of romidepsin treated mouse tumors demonstrated markers of TP53 reactivation. Taken together, our data supports the hypothesis that targeting HDAC2 may represent a potential strategy to modulate MDM2 expression in DDLPS. Impact Journals LLC 2019-10-01 /pmc/articles/PMC6779286/ /pubmed/31620242 http://dx.doi.org/10.18632/oncotarget.27144 Text en Copyright: © 2019 Seligson et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Seligson, Nathan D.
Stets, Colin W.
Demoret, Bryce W.
Awasthi, Achal
Grosenbacher, Nicholas
Shakya, Reena
Hays, John L.
Chen, James L.
Inhibition of histone deacetylase 2 reduces MDM2 expression and reduces tumor growth in dedifferentiated liposarcoma
title Inhibition of histone deacetylase 2 reduces MDM2 expression and reduces tumor growth in dedifferentiated liposarcoma
title_full Inhibition of histone deacetylase 2 reduces MDM2 expression and reduces tumor growth in dedifferentiated liposarcoma
title_fullStr Inhibition of histone deacetylase 2 reduces MDM2 expression and reduces tumor growth in dedifferentiated liposarcoma
title_full_unstemmed Inhibition of histone deacetylase 2 reduces MDM2 expression and reduces tumor growth in dedifferentiated liposarcoma
title_short Inhibition of histone deacetylase 2 reduces MDM2 expression and reduces tumor growth in dedifferentiated liposarcoma
title_sort inhibition of histone deacetylase 2 reduces mdm2 expression and reduces tumor growth in dedifferentiated liposarcoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779286/
https://www.ncbi.nlm.nih.gov/pubmed/31620242
http://dx.doi.org/10.18632/oncotarget.27144
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