A novel histone deacetylase (HDAC) inhibitor MHY219 induces apoptosis via up-regulation of androgen receptor expression in human prostate cancer cells

Patra, Nabanita; De, Umasankar; Kim, Tae Hyung; Lee, Young Ju; Ahn, Mee Young; Kim, Nam Deuk; Yoon, Jung Hyun; Choi, Wahn Soo; Moon, Hyung Ryong; Lee, Byung Mu; Kim, Hyung Sik

doi:10.1016/j.biopha.2013.01.006

Cited by 22 publications

(18 citation statements)

References 42 publications

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“…The present study demonstrated that MHY2256 significantly increased G1 in MCF-7 cells via decreased expression of cyclin D1, CDK2, and CDK4. Previous studies indicated that the CDK inhibitor p21 was up-regulated via p53-dependent and p53-independent mechanisms of HDAC inhibitors 42-45. Similarly, our data indicate that MHY2256 significantly increase the expression of p21 in MCF-7cells but not SKOV-3 cells.…”

Section: Discussionsupporting

confidence: 77%

Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding

Park¹,

Woo²,

Kim³

et al. 2016

Int. J. Biol. Sci.

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The sirtuins (SIRTs), a family of NAD+-dependent class III histone deacetylase, are involved in various biological processes including cell survival, division, senescence, and metabolism via activation of the stress-response pathway. Recently, inhibition of SIRTs has been considered a promising anticancer strategy, but their precise mechanisms of action are not well understood. In particular, the relevance of p53 to SIRT-induced effects has not been fully elucidated. We investigated the anticancer effects of a novel SIRT inhibitor, MHY2256, and its efficacy was compared to that of salermide in MCF-7 (wild-type p53) and SKOV-3 (null-type p53) cells. Cell viability, SIRT1 enzyme activity, cell cycle regulation, apoptosis, and autophagic cell death were measured. We compared sensitivity to cytotoxicity in MCF-7 and SKOV-3 cells. MHY2256 significantly decreased the viability of MCF-7 (IC50, 4.8 μM) and SKOV-3 (IC50, 5.6 μM) cells after a 48 h treatment period. MHY2256 showed potent inhibition (IC50, 0.27 mM) against SIRT1 enzyme activity compared with nicotinamide (IC50, >1 mM). Moreover, expression of SIRT (1, 2, or 3) protein levels was significantly reduced by MHY2256 treatment in both MCF-7 and SKOV-3 cells. Flow cytometry analysis revealed that MHY2256 significantly induced cell cycle arrest in the G1 phase, leading to an effective increase in apoptotic cell death in MCF-7 and SKOV-3 cells. A significant increase in acetylated p53, a target protein of SIRT, was observed in MCF-7 cells after MHY2256 treatment. MHY2256 up-regulated LC3-II and induced autophagic cell death in MCF-7 cells. Furthermore, MHY2256 markedly inhibited tumor growth in a tumor xenograft model of MCF-7 cells. These results suggest that a new SIRT inhibitor, MHY2256, has anticancer activity through p53 acetylation in MCF-7 human breast cancer cells.

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Section: Discussionsupporting

confidence: 77%

Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding

Park¹,

Woo²,

Kim³

et al. 2016

Int. J. Biol. Sci.

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“…MHY219 significantly induced G2/M phase arrest in DU145 and PC3 cells and arrested the cell cycle at G0/G1 phase in LNCaP cells. Furthermore, MHY219 effectively increased apoptosis in DU145 and LNCaP cells 41 (Figure 2B). A248, a novel synthetic HDAC inhibitor, decreased the expression of survivin and Mcl-1 through suppressing specificity protein 1 (Sp1) expression.…”

Section: Hdacs and Prostate Cancermentioning

confidence: 93%

Histone Deacetylases and Mechanisms of Regulation of Gene Expression

2015

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In recent years, it has become widely recognized that histone modification plays a pivotal role in controlling gene expression, and is involved in a wide spectrum of disease regulation. Histone acetylation is a major modification that affects gene transcription and is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDAC). HATs acetylate lysines of histone proteins, resulting in relaxation of chromatin structure, and they also facilitate gene activation. Conversely, HDACs remove acetyl groups from hyperacetylated histones and suppress general gene transcription. In addition to histones, numerous non-histone proteins can be acetylated and deacetylated, and they are also involved in a wide range of disease regulation. To date, there are 18 HDACs in mammals classified into four classes based on homology to yeast HDACs. Accumulating evidence has revealed that HDACs play crucial roles in a variety of biological processes including inflammation, cell proliferation, apoptosis, and carcinogenesis. In this review, we summarize the current state of knowledge of HDACs in carcinogenesis and describe the involvement of HDACs in cancer-associated molecular processes. It is hoped than our understanding of the role of HDACs in cancer will lead to the design of more potent and specific drugs targeting selective HDAC proteins for the treatment of the disease.

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“…It is known that HDAC inhibitors are among the most promising targeted anticancer agents and are potent inducers of growth arrest, differentiation, and autophagic cell death of prostate cells [123] . Very recently, Patra et al [124] developed a novel HDAC inhibitor (MHY219) that induced cancer cell death and might be employed as a chemotherapy adjuvant in clinical studies. Similarly, other HDAC inhibitors have been tested in prostate cancer studies [125][126][127] .…”

Section: Novel Molecular Actors For Autophagy Tuning In Prostate Cancmentioning

confidence: 99%

Prostate cancer cells at a therapeutic gunpoint of the autophagy process

Gabriele¹,

Martinelli²,

Comincini³

2018

JCMT

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In a normal prostate, the process of controling cell death is essential to maintain tissue homeostasis and its inhibition may lead to the development of cancer. Androgen receptor signaling plays pivotal roles in the prostate development and homeostasis as well as in the progression of prostate cancer. The main treatment for prostate cancer is a combination of androgen deprivation therapy (ADT) using anti-androgens and docetaxil administration. However, ADT eventually fails due to a pathological unbalance of cell death processes, in particular apoptosis and autophagy. As a result prostate tumors may re-grow and progress into the castration resistant stage. The role of autophagy in tumorigenesis is complex and it could be a double-edged sword process, as autophagy defects promote cancer progression in association with various dangerous cellular processes, while functional autophagy enables cancer cell survival under stress and likely contributes to the resistance of treatment. Autophagy is often impaired in prostate cancer, due to either activation of the Akt/mTOR pathway, which normally inhibits autophagy, or through allelic loss of Beclin-1 (BECN1), an essential autophagy gene. In particular, elucidating the interplay between autophagy and tumor cell metabolism will provide unique opportunities to identify new therapeutic targets and to develop synthetically lethal treatment strategies that preferentially target cancer cells, while sparing normal tissues.

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A novel histone deacetylase (HDAC) inhibitor MHY219 induces apoptosis via up-regulation of androgen receptor expression in human prostate cancer cells

Cited by 22 publications

References 42 publications

Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding

Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding

Histone Deacetylases and Mechanisms of Regulation of Gene Expression

Prostate cancer cells at a therapeutic gunpoint of the autophagy process

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