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

• Published in: Oncotarget Vol. 10; no. 55; pp. 5671 - 5679
• Main Authors: Seligson, Nathan D., Stets, Colin W., Demoret, Bryce W., Awasthi, Achal, Grosenbacher, Nicholas, Shakya, Reena, Hays, John L., Chen, James L.
• Format: Journal Article
• Language: English
• Published: Impact Journals LLC 01-10-2019
• Subjects: Research Paper
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.27144

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.