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

Ou WB, Zhu J, Eilers G, Li X, Kuang Y, Liu L, Mariño-Enríquez A, Yan Z, Li H, Meng F, Zhou H, Sheng Q, Fletcher JA - Oncotarget (2015)

Bottom Line: 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.Moreover, the pro-apoptotic and anti-proliferative effect of HDACi warrants further evaluation as a therapeutic strategy in MDM2-amplified LPS.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.

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.

No MeSH data available.


Related in: MedlinePlus

Immunoblotting evaluation of the effect of HDAC inhibitors (100 nM LBH589 and 5 μM SAHA) on expression of MDM2, p53, PTEN, CDK4 and JUN in liposarcoma total cell lysates after 48 hours of treatment in serum-containing mediumAcetyl-Histone 3 and Acetyl-tubulin are two acetylation biomarkers. β-actin stain is a loading control.
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Figure 2: Immunoblotting evaluation of the effect of HDAC inhibitors (100 nM LBH589 and 5 μM SAHA) on expression of MDM2, p53, PTEN, CDK4 and JUN in liposarcoma total cell lysates after 48 hours of treatment in serum-containing mediumAcetyl-Histone 3 and Acetyl-tubulin are two acetylation biomarkers. β-actin stain is a loading control.

Mentions: We evaluated the effects of HDACi on MDM2, p53, PTEN, CDK4, and JUN by immunoblotting in LPS lines by treating with HDACi (LBH589 and SAHA) for 48 hours (Figure 2). LBH589 (100 nM) and SAHA (5 μM) depleted MDM2 and p53, and induced PTEN and acetyl H3 in all LPS lines (Figure 2). Treatment with LBH589 and SAHA had little impact on CDK4 and JUN. HDAC inhibition induced acetyl tubulin in LPS778 and LPS510, but showed little effect in LPS141 and isogenic LPS141/239 and LPS141/266 (Figure 2).


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

Ou WB, Zhu J, Eilers G, Li X, Kuang Y, Liu L, Mariño-Enríquez A, Yan Z, Li H, Meng F, Zhou H, Sheng Q, Fletcher JA - Oncotarget (2015)

Immunoblotting evaluation of the effect of HDAC inhibitors (100 nM LBH589 and 5 μM SAHA) on expression of MDM2, p53, PTEN, CDK4 and JUN in liposarcoma total cell lysates after 48 hours of treatment in serum-containing mediumAcetyl-Histone 3 and Acetyl-tubulin are two acetylation biomarkers. β-actin stain is a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496371&req=5

Figure 2: Immunoblotting evaluation of the effect of HDAC inhibitors (100 nM LBH589 and 5 μM SAHA) on expression of MDM2, p53, PTEN, CDK4 and JUN in liposarcoma total cell lysates after 48 hours of treatment in serum-containing mediumAcetyl-Histone 3 and Acetyl-tubulin are two acetylation biomarkers. β-actin stain is a loading control.
Mentions: We evaluated the effects of HDACi on MDM2, p53, PTEN, CDK4, and JUN by immunoblotting in LPS lines by treating with HDACi (LBH589 and SAHA) for 48 hours (Figure 2). LBH589 (100 nM) and SAHA (5 μM) depleted MDM2 and p53, and induced PTEN and acetyl H3 in all LPS lines (Figure 2). Treatment with LBH589 and SAHA had little impact on CDK4 and JUN. HDAC inhibition induced acetyl tubulin in LPS778 and LPS510, but showed little effect in LPS141 and isogenic LPS141/239 and LPS141/266 (Figure 2).

Bottom Line: 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.Moreover, the pro-apoptotic and anti-proliferative effect of HDACi warrants further evaluation as a therapeutic strategy in MDM2-amplified LPS.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.

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.

No MeSH data available.


Related in: MedlinePlus