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

Our plain-English summary of HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN, irrespective of p53 mutational status, by W.B. Ou, J. Zhu, G. Eilers, et al (Oncotarget, 2015).

The study

• Authors: W.B. Ou, J. Zhu, G. Eilers, X. Li, Y. Kuang, L. Liu, A. Mariño-Enríquez, Z. Yan, H. Li, F. Meng, H. Zhou, Q. Sheng, J.A. Fletcher
• Journal: Oncotarget
• Published: 2015;6(12):10510-20
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study of human cancer cells grown in culture. It did not study asbestos exposure or patients. The authors tested two HDAC inhibitor drugs, LBH589 (panobinostat) and SAHA (vorinostat), on several liposarcoma cell lines and on three mesothelioma cell lines used as controls. In the liposarcoma lines, both drugs lowered the proteins MDM2 and p53 and raised PTEN, with little impact on CDK4 and JUN. In the mesothelioma line JMN1B, which carries a p53 mutation, the drugs broke down the mutant p53. In MESO924 and MESO296, which have normal p53, they had minimal effect on MDM2 and p53. Both drugs strongly reduced growth of all liposarcoma and mesothelioma lines and induced apoptosis (a form of cell death) in all lines. Reducing MDM2 and p53 together with shRNA, a technique that lowers rather than fully removes a gene's activity, cut viability by 40–80% in three p53-mutant liposarcoma lines. The authors concluded that HDAC inhibitors warrant clinical evaluation in liposarcoma with mutant p53. They also suggested the approach might be effective in mesothelioma, especially p53-mutant sublines.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of human cancer cell lines; no patients or animals
• Who was studied: Human liposarcoma cell lines (LPS141, LPS141/239, LPS141/266, LPS449, LPS778, LPS510) and mesothelioma cell lines (MESO924, MESO296, JMN1B). Most of the liposarcoma lines were developed at Brigham and Women's Hospital, and the mesothelioma lines were established in the Fletcher laboratory.
• Exposure: No asbestos exposure was studied. The cells were treated with the HDAC inhibitors LBH589 (panobinostat) and SAHA (vorinostat) and with the MDM2 antagonist Nutlin-3. MDM2 and p53 levels were also reduced with shRNA knockdown.
• Main results:
  • Nutlin-3 had only minor effects (5–15% reduction in proliferation) in the p53-mutant liposarcoma lines LPS141/239, LPS141/266 and LPS510. By contrast, it dramatically inhibited the p53 wild-type lines LPS778 and LPS141.
  • In all liposarcoma lines, LBH589 (100 nM) and SAHA (5 μM) depleted MDM2 and p53 and induced PTEN. They had little impact on CDK4 and JUN.
  • In the mesothelioma lines MESO924 and MESO296 (normal MDM2, wild-type p53), the HDAC inhibitors had minimal effect on MDM2 and p53. In p53-mutant JMN1B, they degraded mutant p53 but had little effect on MDM2.
  • Cell proliferation was strongly inhibited in all liposarcoma and mesothelioma lines in a dose-dependent manner. IC50 values for LBH589 and SAHA were 520 nM and 3.8 μM in MESO924, 540 nM and 4.7 μM in MESO296, and 52 nM and 3.7 μM in JMN1B.
  • Treatment with LBH589 and SAHA for 48 hours induced apoptosis in all cell lines.
  • The HDAC inhibitors inactivated AKT in the liposarcoma lines LPS510 and LPS778 and in the mesothelioma lines MESO924 and MESO296.
  • The shRNA knockdown reduced MDM2 and p53 levels by more than 60% with at least one construct. It did not completely eliminate them.
  • Combined MDM2 and p53 knockdown reduced cell viability by 40–80% in three p53-mutant liposarcoma lines. This was a greater effect than either knockdown alone. Viability data were normalized to empty-vector controls.
• The authors' conclusion: The authors concluded that HDAC inhibitors warrant clinical evaluation as a therapeutic strategy in liposarcoma with mutant p53. They also stated that their data add to evidence that this approach might be effective in mesothelioma, especially p53-mutant sublines.
• Limitations the authors state:
  • The authors stated that the mechanism by which the HDAC inhibitors increased PTEN is unclear.

Topics

Medical terms in this study, explained in our Lexicon: Well-Differentiated, Apoptosis, Mesothelioma.

Related studies

• Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype — X. Ning, T.T.T. Nguyễn, et al. (2026)
• An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression — T.T.T. Nguyen, M. Shingyoji, et al. (2021)
• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• Downregulation of cyclin D1 sensitizes cancer cells to MDM2 antagonist Nutlin-3 — P. Yang, W. Chen, et al. (2016)
• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)
• Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists — L. Urso, I. Cavallari, et al. (2017)

Browse more research in Oncotarget, or return to medical research.