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

// Nathan D. Seligson 1 , * , Colin W. Stets 2 , * , Bryce W. Demoret 2 , Achal Awasthi 2 , Nicholas Grosenbacher 2 , Reena Shakya 3 , John L. Hays 4 , 5 and James L. Chen 2 , 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 ABSTRACT 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. HDAC 2 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.