Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53

Mrakovcic, Maria; Kleinheinz, Johannes; Fröhlich, Leopold F.

doi:10.3390/ijms18091883

Cited by 42 publications

(50 citation statements)

References 222 publications

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“…Our experimental evidence thus underlines an overall major regulatory role for p53 not only in HDACi-mediated apoptosis but also in HDACi-stimulated autophagy (Figure 3) (reviewed in [57,141]). As a consequence, p53-deficiency could moreover explain apoptosis resistance as well predominant induction of HDACi-provoked autophagy in cancer cells.…”

Section: Hdaci-induced Autophagy Mediated By P53supporting

confidence: 58%

“…An impressive diversity of mechanisms have been uncovered in cancer cells that promote HDACi-elicited autophagy which include mostly attenuation of mTOR signaling that can occur in combination combined with increased expression of LC3, Beclin-1, or ATG and can be provoked by endoplasmic reticulum stress (reviewed in [57] and Table 1 [141]). mTOR is a well-known regulator of the canonical pathway of autophagy involving the regulation of the ULK1 complex and Beclin-1.…”

Section: Mechanisms Of Hdaci-induced Autophagic Cell Deathmentioning

confidence: 99%

“…Conclusively, p53-dependent but also -independent signaling pathways may add to HDACi-mediated apoptotic processes and HDACi may induce p53, but do not unconditionally require p53 for providing anticancer effects. In recent time, the range of HDACi-exerted mechanisms resulting in cellular demise of cancer cells have been expanded by the induction of autophagic cell death which can alternatively or additionally to apoptosis activate autophagy (reviewed in [57,141,172] and Table 1). Also, involvement of posttranslational modification of the non-histone p53 has been linked to the control of HDACi-stimulated autophagy as evident from its key regulatory role in normal cells.…”

Section: Hdaci-induced Autophagy Mediated By P53mentioning

confidence: 99%

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Regulation of HDACi−Triggered Autophagy by the Tumor Suppressor Protein p53

Mrakovcic¹,

Fröhlich²

2019

Genes and Cancer

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Cancer is a complex genetic and epigenetic-based disease that has developed a multitude of mechanisms in evading cell death. Deregulation of apoptosis and autophagy are commonly encountered during the development of human tumors. Histone deacetylase inhibitors (HDACi) have been employed to reverse epigenetically deregulated gene expression caused by aberrant post-translational protein modifications. These interfere with histone acetyltransferase-and deacetylasemediated acetylation of histone and non-histone proteins, and thereby exert a wide array of HDACi-stimulated cytotoxic effects. Key determinants of HDACi lethality that interfere with cellular growth in a multitude of tumor cells are apoptosis and autophagy. Currently, the factors that determine the mode of HDACi-elicited cell death are mostly unclear however. Experimental evidence of the last decade convincingly reports that the frequently mutated tumor suppressor protein p53 can act either as an activator or as an inhibitor of autophagy depending on its subcellular localization, and linked to its mode of action. Consistently, we recently described p53 as a regulatory switch that governs if histone deacetylase inhibitor-administered uterine sarcoma cells undergo autophagy or apoptosis. By highlighting this novel finding, we summarize in this chapter the role of p53-mediated signaling during the activation of the autophagic pathway in tumor cells in response to HDACi.

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Section: Hdaci-induced Autophagy Mediated By P53supporting

confidence: 58%

Section: Mechanisms Of Hdaci-induced Autophagic Cell Deathmentioning

confidence: 99%

Section: Hdaci-induced Autophagy Mediated By P53mentioning

confidence: 99%

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Regulation of HDACi−Triggered Autophagy by the Tumor Suppressor Protein p53

Mrakovcic¹,

Fröhlich²

2019

Genes and Cancer

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“…Substantial evidence has shown the ability of pan-HDAC inhibitors to promote autophagy [26,27]. During autophagy, the formation of acidic vesicular organelles (AVOs) is one of the characteristic features of cells engaged in autophagy in response to starvation or radiation [28].…”

Section: Hmc Induces Autophagymentioning

confidence: 99%

Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor

et al. 2019

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Epigenetic therapy has been demonstrated to be a viable strategy for breast cancer treatment. In this study, we report the anti-tumor activity of a hydroxamate-based histone deacetylase (HDAC)8-selective inhibitor, HMC, in breast cancer cells. MTT assays showed that HMC inhibited cell viability of MCF-7 and MDA-MB-231 cells with IC 50 values of 7.7 µM and 9.5 µM, respectively. HMC induced caspase-dependent apoptosis in MCF-7 cells, which was associated with its ability to modulate a series of cell survival-related signaling effectors, including Akt, mTOR, Bax, Mcl-1, and Bcl-2. Additionally, HMC was capable of activating PPARγ, which was accompanied by reduced expression of PPARγ target gene products, such as cyclin D1 and CDK6. HMC increased the production of ROS in MCF-7 cells, which could be partially reversed by the cotreatment with a ROS scavenger (N-acetylcysteine or glutathione). Furthermore, HMC induced autophagy, as characterized by the formation of acidic vesicular organelles and autophagic biomarkers including LC3B-II and Atg5. Notably, pharmacological blockade of autophagy by 3-MA or CQ could attenuate HMC-induced apoptosis, suggesting that autophagy played a self-protective role in HMC-induced cell death. Together, these data suggest the translational potential of HMC to be developed into a potential therapeutic agent for breast cancer therapy.

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“…Over the last few years, the link between autophagic process regulation and HDACs or HDAC inhibitor (HDACi) has been gradually noticed (18). Inconsistently, autophagy modulation by HDACs or HDACi was pleiotropic in a cell type-dependent manner (19). For example, in HeLa cells, HDACi FK228 induced autophagic vacuole formation and lysosome function (20), whereas Cao et al (21) found that HDACi trichostatin A (TSA) suppressed autophagic activation and attenuated hypertrophic growth in cultured cardiomyocyte.…”

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confidence: 99%

STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy

Wang

et al. 2019

FASEB j.

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Schwann cells are the main supportive cells of the peripheral nerves. Schwann cells suffer inhibition of autophagy under hyperglycemia treatment in diabetic peripheral neuropathy (DPN). However, the exact mechanism is still not fully elucidated. We first observed the decrease of autophagy markers (LC3‐II/LC3‐I, P62) in the sciatic nerves of diabetic mice vs. normal mice, accompanied with the loss of myelinated nerve fibers and abnormal myelin sheath. In line with this, LC3‐II/LC3‐I and P62 were also significantly reduced in high glucose—treated rat Schwann cell 96 (RSC96) cells compared with normal glucose—treated cells. Furthermore, we found that trichostatin A [an inhibitor of histone deacetylase (HDAC)] evidently improved LC3‐II/LC3‐I in high glucose—treated RSC96 cells, without an effect on P62 expression. Again, HDAC1 and HDAC5 were revealed to be increased in RSC96 cells stimulated with high glucose. Inhibition of HDAC1 but not HDAC5 by small hairpin RNA vector enhanced LC3‐II/LC3‐I in high glucose—cultured RSC96 cells. In addition, LC3‐II conversion regulators [autophagy‐related protein (Atg)3, Atg5, and Atg7] were detected in high glucose—treated and HDAC1‐knockdown RSC96 cells, and Atg3 was proven to be the key target of HDAC1. The presuppression of Atg3 offset the improvement of LC3‐II/LC3‐I resulting from HDAC1 inhibition in high glucose—treated RSC96 cells. The Janus kinase (JAK)—signal transducer and activator of transcription (STAT) signaling pathway was activated in RSC96 cells treated with high glucose, which was indicated by increased STAT3 phosphorylation. Blocking STAT3 phosphorylation by chemical inhibitor AG490 induced HDAC1 down‐regulation followed by increases in Atg3 and LC3‐II/LC3‐I. Interestingly, we also found that AG490 treatment enhanced P62 expression in high glucose—stimulated RSC96 cells. Taken together, our findings demonstrate that hyperglycemia inhibits LC3‐II/LC3‐I in an HDAC1‐Atg3—dependent manner and decreases P62 expression in an HDAC‐independent manner via the JAK‐STAT3 signaling pathway in the Schwann cells of DPN.—Du, W., Wang, N., Li, F. Jia, K., An, J., Liu, Y., Wang, Y., Zhu, L., Zhao, S. Hao, J. STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy. FASEB J. 33, 8008–8021 (2019). http://www.fasebj.org

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Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53

Cited by 42 publications

References 222 publications

Regulation of HDACi−Triggered Autophagy by the Tumor Suppressor Protein p53

Regulation of HDACi−Triggered Autophagy by the Tumor Suppressor Protein p53

Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor

STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy

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