Research Papers:

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

Nathan D. Seligson, Colin W. Stets, Bryce W. Demoret, Achal Awasthi, Nicholas Grosenbacher, Reena Shakya, John L. Hays and James L. Chen _

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Oncotarget. 2019; 10:5671-5679. https://doi.org/10.18632/oncotarget.27144

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Nathan D. Seligson1,*, Colin W. Stets2,*, Bryce W. Demoret2, Achal Awasthi2, Nicholas Grosenbacher2, Reena Shakya3, John L. Hays4,5 and James L. Chen2,4

1 Department of Pharmacy, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, Ohio, USA

2 Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA

3 Target Validation Shared Resource, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, Ohio, USA

4 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA

5 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio, USA

* These authors contributed equally to this work

Correspondence to:

James L. Chen,email: James.Chen@osumc.edu

Keywords: dedifferentiated liposarcomas; MDM2; HDAC2; romidepsin; MI-192

Received: June 12, 2019     Accepted: July 21, 2019     Published: October 01, 2019


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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