Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cells

Agarwal, Soumik; Amin, Karishma S.; Jagadeesh, Shankar; Baishay, Gokul; Rao, Paruchuri G.; Barua, Nabin C.; Bhattacharya, Samir; Banerjee, Partha P.

doi:10.1186/1476-4598-12-99

Cited by 100 publications

(91 citation statements)

References 35 publications

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“…In addition to Western drugs, phytochemicals have also been found to possess chemoprevention effects via epigenetic alterations (15). For example, mahanine, a carbazole alkaloid found abundantly in some Asian vegetables, has been reported to be a DNA hypomethylation agent that restored the expression of an epigenetically silenced tumor suppressor gene due to the inhibitory effect of DNMTs (16).…”

Section: Introductionmentioning

confidence: 99%

Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway

Wang

Zhang

Guo

et al. 2014

AAPS J

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Abstract. Increasing numbers of natural products have been found to possess anticancer effects. Nuclear factor erythroid-2-related factor-2 (Nrf2) is a master regulator of the antioxidative stress response, and our previous studies found that epigenetic modification of the Nrf2 gene appears to be a critical mechanism. Salvia miltiorrhiza, a Chinese herbal medicine widely used in Asian countries, has been shown to possess anticancer and antioxidant effects. Tanshinone IIA (TIIA), an active component in S. miltiorrhiza, has been reported to activate Nrf2 pathway. The objective of this study was to investigate the epigenetic regulation of Nrf2 by TIIA in mouse skin epidermal JB6 cells and the functional consequences for cell transformation. TIIA was found to induce antioxidant response element-luciferase and upregulate the mRNA and protein levels of Nrf2 and Nrf2 downstream target genes HO-1 and NQO-1. TIIA decreased the colony formation of JB6 cells by approximately 80%. TIIA decreased the protein levels of DNMT1, DNMT3a, DNMT3b, and HDAC3 and inhibited the enzymatic activity of HDACs. Bisulfite genomic sequencing indicated that TIIA demethylated the first five CpGs in the promoter region of the Nrf2 gene. Chromatin immunoprecipitation assays showed that TIIA treatment increased the recruitment of RNA polymerase II at Nrf2 transcription start site but had limited effects on enrichment of Ac-H3 in Nrf2 promoter. Taken together, our results show that TIIA activates the Nrf2 signaling pathway and induces epigenetic demethylation of the CpGs of Nrf2. The epigenetic reactivation of the Nrf2 signaling pathway by TIIA could potentially contribute to the attenuation of JB6 cellular transformation and anticancer effects.

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Section: Introductionmentioning

confidence: 99%

Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway

Wang

Zhang

Guo

et al. 2014

AAPS J

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“…Mahanine did not induce degradation of DNMT3B and DNMT1 in constitutively active Akt-expressing cells, suggesting that mahanine exerted inhibitory effects on wild-type Akt. 9 Similarly, hepatitis B virus X protein (HBx; HBVgp3) negatively regulates RASSF1A. For example, HBx-positive cells markedly reduce RASSF1A expression and are associated with markedly higher expression of DNMT3B and DNMT1.…”

Section: Dnmt-mediated Inactivation Of Rassf1amentioning

confidence: 99%

“…12,13 Regulation of RASSF1A is thought to be mediated by DNMT proteins in responses to natural products and to viral infection. 9 For example, mahanine, a plant-derived carbazole alkaloid, was reported to restore expression of RASSF1A in prostate cancer cells. Mechanistically, it was shown that mahanine induced DNMT3B and DNMT1 degradation and reduced nuclear accumulation of both these enzymes.…”

Section: Dnmt-mediated Inactivation Of Rassf1amentioning

confidence: 99%

Epigenetic mechanisms in cancer: push and pull between kneaded erasers and fate writers

Farooqı¹,

Tang²,

Li³

et al. 2015

IJN

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Research concerning the epigenome over the years has systematically and sequentially shown substantial development and we have moved from global inhibition of modifications of the epigenome toward identification and targeted therapy against tumor-specific epigenetic mechanisms. In accordance with this approach, several drugs with epigenetically modulating activity have received considerable attention and appreciation, and recently emerging scientific evidence is uncovering details of their mode of action. High-throughput technologies have considerably improved our existing understanding of tumor suppressors, oncogenes, and signaling pathways that are key drivers of cancer. In this review, we summarize the general epigenetic mechanisms in cancer, including: the post-translational modification of DNA methyltransferase and its mediated inactivation of Ras association domain family 1 isoform A, Sonic hedgehog signaling, Wnt signaling, Notch signaling, transforming growth factor signaling, and natural products with epigenetic modification ability. Moreover, we introduce the importance of nanomedicine for delivery of natural products with modulating ability to epigenetic machinery in cancer cells. Such in-depth and comprehensive knowledge regarding epigenetic dysregulation will be helpful in the upcoming era of molecular genomic pathology for both detection and treatment of cancer. Epigenetic information will also be helpful when nanotherapy is used for epigenetic modification.

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“…The actives were positive controls or compounds that showed inhibitory activity against DNMT1 through in vitro or in vivo tests. Based on the previous research, 25 compounds were chosen as actives [11][12][13][14][15][16][17]. Their structures were obtained in SMILES format from the PubChem website at pubchem.ncbi.nlm.nih.gov [33].…”

Section: Preparing the Ligand Structurementioning

confidence: 99%

“…Natural products are promising non-nucleoside DNMTi candidates because of their relatively low toxicity and high structural diversity [10,11]. The potential of several natural products has been studied; these products have included curcumin [12], epigallocatechin (EGCG) [13], genistein [14], caffeic acid [15], psammaplin A [16], mahanine [17], and laccaic acid [16]. However, the inhibitory effects of these natural compounds are relatively low [11].…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening of Indonesian Herbal Database for Dna Methyltransferase Inhibitors

Bhaskarawilaputraka

Azminah

Erlina

et al. 2017

Asian J Pharm Clin Res

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Objective: DNA hypermethylation is an abnormal epigenetic process catalyzed by DNA methyltransferase 1 (DNMT1). It is also one of the factors that cause non-communicable diseases such as cancer, diabetes, and other metabolic diseases. DNA hypermethylation can be reversed by suppressing DNMT1 activity using a DNMT inhibitor. This study was conducted to seek out inhibitor candidates among natural products. Methods:The search for potential inhibitors was conducted through a virtual screening of the Indonesian Herbal Database using AutoDockVina as docking software. Twenty-five compounds known for their inhibitory activity against DNMT1 were used as actives and as a reference for generating decoys, which was done using the Directory of Useful Decoys, Enhanced. Results:The 12 compounds with binding energies below the cutoff value were cassiamin C (A1), procyanidin B2 (B2), ent-epicatechin-(4alpha->8)-ent-epicatechin (C3), epicatechin-(4beta->8)-epicatechin-3-O-gallate (D4), neorhusflavanone (E5), 3-O-galloylepicatechin-(4beta->6)-epicatechin-3-O-gallate (F6), withanolide (G7), 3-O-galloylepigallocatechin-(4beta->6)-epigallocatechin-3-O-gallate (H8), cyanidin 3-(6''-caffeylsophoroside)-5-glucoside (I9), epifriedelanol (J10), gallocatechin-(4alpha->8)-epicatechin (K11), and scutellarein 7-glucosyl-(1->4)-rhamnoside (L12). A1 had the lowest binding energy of −12.7 kcal/mol, whereas K11 had the highest of −11.5 kcal/mol. Conclusions:The virtual screening yielded five potential DNMT1 inhibitors: Procyanidin B2, ent-epicatechin-(4alpha->8)-ent-epicatechin, epicatechin-(4beta->8)-epicatechin-3-O-gallate, neorhusflavanone, and cyanidin 3-(6''-caffeylsophoroside)-5-glucoside.Keywords: Epigenetic, DNA methyltransferase inhibitor, Indonesian Herbal Database, Virtual screening, AutoDockVina. INTRODUCTIONEpigenetic modification is one of the factors that cause noncommunicable diseases. Living environment, lifestyle, exposure to toxic chemicals, and nutrition may influence an individual's epigenetic profile. Epigenetic modification can alter gene expression [1]. One type of epigenetic modification is DNA methylation. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), is the addition of a methyl (CH3) group to the DNA strand, specifically to the fifth carbon atom of a cytosine ring. Methylated cytosine, called 5-methylcytosine, usually occurs to a cytosine base that lies adjacent to a guanine base, at what is called a CpG site. The reason for this name is that cytosine is bonded to guanine through a phosphate bond. These sites normally occur in clusters; an area rich in CpG sites is called a CpG island. CpG islands are usually located near a gene regulator such as a promoter. DNA methylation that affects a gene promoter may repress the transcription of said gene and ultimately its expression. This process of turning a gene on and off through methylation is part of normal eukaryotic cell function [2,3].There are several types of DNMTs. Based on their functions, they can be grouped into two categories: De novo DNMTs...

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Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cells

Cited by 100 publications

References 35 publications

Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway

Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway

Epigenetic mechanisms in cancer: push and pull between kneaded erasers and fate writers

Virtual Screening of Indonesian Herbal Database for Dna Methyltransferase Inhibitors

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