HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN, irrespective of p53 mutational status

Abstract

// Wen-Bin Ou 1, 2, 3 , Jiaqing Zhu 1 , Grant Eilers 3 , Xuhui Li 2 , Ye Kuang 1 , Li Liu 2 , Adrián Mariño-Enríquez 3 , Ziqin Yan 2 , Hailong Li 2 , Fanguo Meng 2 , Haimeng Zhou 2 , Qing Sheng 1 , Jonathan A. Fletcher 3 1 College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China 2 Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, Zhejiang, China 3 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA Correspondence to: Wen-Bin Ou, e-mail: ouwenbin@tsinghua.org.cn Keywords: liposarcoma, HDACi, MDM2 amplification, PTEN, p53 mutation Received: December 01, 2014      Accepted: January 28, 2015      Published: March 23, 2015 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.