Oncotarget

Research Papers:

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

Wen-Bin Ou _, Jiaqing Zhu, Grant Eilers, Xuhui Li, Ye Kuang, Li Liu, Adrián Mariño-Enríquez, Ziqin Yan, Hailong Li, Fanguo Meng, Haimeng Zhou, Qing Sheng and Jonathan A. Fletcher

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2015; 6:10510-10520. https://doi.org/10.18632/oncotarget.3230

Metrics: PDF 2326 views  |   HTML 2833 views  |   ?  


Abstract

Wen-Bin Ou1,2,3, Jiaqing Zhu1, Grant Eilers3, Xuhui Li2, Ye Kuang1, Li Liu2, Adrián Mariño-Enríquez3, Ziqin Yan2, Hailong Li2, Fanguo Meng2, Haimeng Zhou2, Qing Sheng1, Jonathan A. Fletcher3

1College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China

2Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, Zhejiang, China

3Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

Correspondence to:

Wen-Bin Ou, e-mail: [email protected]

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 3230