Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

Zheng, Shunsheng; Koh, Xin Yu; Goh, Hui Chin; Rahmat, Siti Aishah Binte; Hwang, Le-Ann; Lane, David P.

doi:10.1158/0008-5472.can-17-0424

Cited by 16 publications

(14 citation statements)

References 47 publications

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“…Among these downstream targets are p21 and PUMA, which are major mediators of the function of p53 (41). Previous studies performed on other cancer cell lines have demonstrated that HDAC inhibition results in the upregulation of p21 and PUMA expression through increasing the acetylation of p53 (20,21,42). In the present study, AR-42 increased p21 and PUMA expression, confirming p53 activation; therefore, AR-42 treatment may successfully induce molecular mediators of cell cycle arrest and apoptosis.…”

Section: Discussionsupporting

confidence: 81%

Histone deacetylase inhibitor AR‑42 inhibits breast cancer cell growth and demonstrates a synergistic effect in combination with 5‑FU

Zhou

Tang

et al. 2018

Oncol Lett

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AR-42 is a member of a novelly discovered class of phenylbutyrate-derived histone deacetylase inhibitors, and has a number of antitumor effects in a variety of tumor types; however, the role of AR-42 and its possible mechanisms have not been reported in the treatment of breast cancer. The aim of the present study was to investigate the antitumor effects of AR-42 and its associated mechanisms in breast cancer. MTT assays and colony formation assays were conducted to measure the proliferation of MCF-7 cells, and flow cytometry was used to analyze cell apoptosis. The results revealed that AR-42 induced cell apoptosis and suppressed cell growth in a dose- and time-dependent manner. Mechanistically, AR-42 treatment increased the acetylation of the p53 protein and prolonged the half-life of the p53 protein; furthermore, AR-42 treatment upregulated p21 and PUMA expression. Notably, AR-42 had a synergistic effect on MCF-7 cells in combination with fluorouracil, which is one of the most commonly used chemotherapeutic agents. In conclusion, the results indicated that AR-42 inhibits breast cancer cell proliferation and induces apoptosis, indicating that AR-42 is a potential therapeutic agent.

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Section: Discussionsupporting

confidence: 81%

Histone deacetylase inhibitor AR‑42 inhibits breast cancer cell growth and demonstrates a synergistic effect in combination with 5‑FU

Zhou

Tang

et al. 2018

Oncol Lett

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“…P53 acetylation was correlated with p53 activation during the DNA damage response. To determine the effects of p53 acetylation in M1 polarization, we inhibited the p53 acetylase in macrophages with the p300/CBP inhibitor C646 as Zheng described 20. Figure 4C,D showed that C646 repressed p53 acetylation but did not decrease total p53 level after iron treatment, whereas NAC repressed p53 expression and acetylation.…”

Section: Resultsmentioning

confidence: 99%

Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl‐p53 pathway

et al. 2018

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PurposeMacrophages play critical roles in inflammation and wound healing and can be divided into two subtypes: classically activated (M1) and alternatively activated (M2) macrophages. Macrophages also play important roles in regulating iron homeostasis, and intracellular iron accumulation induces M1‐type macrophage polarization which provides a potential approach to tumor immunotherapy through M2 tumor‐associated macrophage repolarization. However, the mechanisms underlying iron‐induced M1 polarization remain unclear.MethodsWestern blotting, qRT‐PCR, and flow cytometry were used to detect the polarization indexes in RAW 264.7 murine macrophages treated with iron, and Western bloting and qRT‐PCR were used to detect p21 expression. The compound 2,7‐dichlorofluorescein diacetate was used to measure reactive oxygen species (ROS) levels in macrophages after iron or N‐acetyl‐l‐cysteine (NAC) treatment. The p300/CREB‐binding protein (CBP) inhibitor C646 was used to inhibit p53 acetylation, and Western bloting, qRT‐PCR, and immunofluorescence were used to detect p53 expression and acetylation. BALB/c mice were subcutaneously injected with H22 hepatoma cells, and macrophage polarization status was investigated after tail intravenous injection of iron. Immunohistochemical staining was used to evaluate the protein expression of cluster of differentiation 86 (CD86) and EGF‐like module‐containing mucin‐like hormone receptor‐like 1 (F4/80) in the subcutaneous tumors.ResultsIron overload induced M1 polarization by increasing ROS production and inducing p53 acetylation in RAW cells, and reduction in ROS levels by NAC repressed M1 polarization and p53 acetylation. Inhibition of acetyl‐p53 by a p300/CBP inhibitor prevented M1 polarization and inhibited p21 expression. These results showed that high ROS levels induced by iron overload polarized macrophages to the M1 subtype by enhancing p300/CBP acetyltransferase activity and promoting p53 acetylation.

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“…Post‐translational modifications in p53 are critical processes that have effects on its stability . In response to various genotoxic stresses, p53 is phosphorylated and acetylated at specific residues, thereby resulting in its stabilization and activation . Hence, a number of questions remain unanswered, including how HMGA2 regulates p53 stability through other post‐translational modifications (such as phosphorylation, acetylation, and neddylation).…”

Section: Discussionmentioning

confidence: 99%

HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53

Wang

et al. 2018

The Journal of Pathology

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High mobility group A2 (HMGA2) is an architectural transcription factor that promotes human colorectal cancer (CRC) aggressiveness by modulating the transcription of target genes. The degradation of p53 is mediated by murine double minute 2 (MDM2) in a proteasome-dependent manner. Here we report that HMGA2 promotes cell cycle progression and inhibits apoptosis in CRC cells in vitro. We also developed an intestinal epithelial cell-specific Hmga2 knock-in (KI) mouse model. It revealed that the Hmga2 KI promoted chemical carcinogen-induced tumorigenesis in the intestine in vivo. In studying the underlying molecular mechanism, we found that HMGA2 formed a protein complex with p53. The tetramerization domain of p53 (amino acids 294-393) and the three AT-hook domains (amino acids 1-83) of HMGA2 were responsible for their direct interaction. We also found that HMGA2 directly bound to MDM2 and the central acidic and zinc finger domains of MDM2 (amino acids 111-360) were required for interaction with HMGA2. Furthermore, our results indicated that HMGA2 promoted MDM2-mediated p53 ubiquitination and degradation. Interestingly, Hmga2 overexpression in Hmga2 KI mice resulted in an increase in the accumulation of ubiquitinated p53. In addition, in two large CRC cohorts, it was demonstrated that high HMGA2 expression was predictive of an adverse outcome in the p53-negative subgroup of CRC patients. In summary, our data have established for the first time a novel mechanism by which HMGA2 functions with p53 and MDM2 to promote CRC progression. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

Cited by 16 publications

References 47 publications

Histone deacetylase inhibitor AR‑42 inhibits breast cancer cell growth and demonstrates a synergistic effect in combination with 5‑FU

Histone deacetylase inhibitor AR‑42 inhibits breast cancer cell growth and demonstrates a synergistic effect in combination with 5‑FU

Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl‐p53 pathway

HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53

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