Abstract
The MDM2-p53 pathway plays a prominent role in well-differentiated liposarcoma (LPS) pathogenesis. Here, we explore the importance of MDM2 amplification and p53 mutation in LPS independently, to determine whether HDACi are therapeutically useful in LPS. We demonstrated that simultaneous knockdown of MDM2 and p53 in p53-mutant LPS lines resulted in increased apoptosis, anti-proliferative effects, and cell cycle arrest, as compared to either intervention alone. HDACi treatment resulted in the dephosphorylation and depletion of MDM2 and p53 without affecting CDK4 and JUN expression, irrespective of p53 mutational status in MDM2-amplified LPS. In control mesothelioma cell lines, HDACi treatment resulted in down-regulation of p53 in the p53 mutant cell line JMN1B, but resulted in no changes of MDM2 and p53 in two mesothelioma lines with normal MDM2 and wild-type p53. HDACi treatment substantially decreased LPS and mesothelioma proliferation and survival, and was associated with upregulation of PTEN and p21, and inactivation of AKT. Our findings indicate that wild-type p53 depletion by HDACi is MDM2 amplification-dependent. These findings underscore the importance of targeting both MDM2 and p53 in LPS and other cancers harboring p53 mutations. Moreover, the pro-apoptotic and anti-proliferative effect of HDACi warrants further evaluation as a therapeutic strategy in MDM2-amplified LPS.
Highlights
Liposarcoma (LPS) is the most common human sarcoma, representing 24% of extremity and 45% of retroperitoneal soft tissue sarcoma [1,2,3]
We explore the importance of MDM2 amplification and p53 mutation in LPS independently, to determine whether HDAC inhibitors (HDACi) are therapeutically useful in LPS
We evaluate the effects of the HDACi SAHA and LBH589 on proliferation and survival of LPS and control mesothelioma cell lines
Summary
Liposarcoma (LPS) is the most common human sarcoma, representing 24% of extremity and 45% of retroperitoneal soft tissue sarcoma [1,2,3]. LPS is subdivided into five histopathologic subtypes, including welldifferentiated (WDLPS, ∼50%), dedifferentiated (DDLPS, 9% to 18%), round cell, myxoid, and pleomorphic. Dedifferentiated, round cell and pleomorphic LPS are highgrade, aggressive tumors with significant metastatic potential while WDLPS and myxoid LPS are low-grade tumors that follow a more indolent clinical course [1, 2, 4]. JUN maybe amplified in WDLPS cases with a dedifferentiated component [12], and down-regulation or complete loss of PTEN or an alternative mechanism of PIK3CA mutation results in AKT activation in a subset of LPS [2, 13, 14], implicating the PI3K/AKT/mTOR pathway as a therapeutic target [15]. Inhibition of the MDM2-p53 interaction by Nutlin-3, an antagonist of MDM2, induces apoptosis and growth arrest in p53 wild-type LPS [19, 20]
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