Use of histone methyltransferase inhibitors in cancer treatment: A systematic review

Marzochi, Ludimila Leite; Cuzziol, Caroline Izak; Filho, Carlos Henrique Viesi do Nascimento; Santos, Juliana Amorim dos; Castanhole-Nunes, Márcia Maria Urbanin; Pavarino, Érika Cristina; Guerra, Eliete Neves Silva; Goloni-Bertollo, Eny Maria

doi:10.1016/j.ejphar.2023.175590

Cited by 19 publications

(8 citation statements)

References 52 publications

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“…The clinically relevant inhibitors of epigenetic regulators like histone deacetylases (HDAC)s ( 28, 29 ) and DNA methyltransferases (DNMT) (30) , Histone Methyltransferases (HMTs) (31) , Histone Demethylase (HDMs) (32) , Bromodomain and Extra-Terminal (BET) (33) are well documented. The DNMT inhibitor (DNMTi) and HDAC inhibitor (HDACi) and BET inhibitors (BETi) has already been approved as drugs against selective cancers and entered market for clinical use (34) .…”

Section: Discussionmentioning

confidence: 99%

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Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Nalla,

Chatterjee,

Poyya

et al. 2024

Preprint

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Histone methyltransferases are selectively catalyzing the methylation of lysine or arginine residues of target histone and non-histone proteins, classified as lysine methyltransferases and arginine methyltransferases. The EZH2 and PRMT5 catalyze trimethylation of H3 at K27 and symmetric dimethylation of H4 at R3 respectively. These histone repressive marks have been considered as hallmarks in cancer. Both PRMT5 and EZH2 over expressed in several cancers and have been considered as important target of drug development. As a result, many synthetic molecules as inhibitors of both PRMT5 and EZH2 are at different level of preclinical and clinical phases. Cancer atlas data analysis revealed that both PRMT5 and EZH2 had shown more than 90% amplification in breast cancer alone. We screened an array of phytocompounds towards the inhibition of PRMT5 and EZH2 usingin silico, in vitroassays. Among them Epigallocatechin-3-gallate (EGCG) has interacted with human PRMT5: MEP50 and EZH2 efficiently. The EGCG interacted within the SAM binding site, with a π-cation interaction at Lys 333 and H-bonds with Tyr324, Tyr334, Gly365, Leu437, and Glu444. Surface plasmon resonance analysis revealed that EGCG has strong binding affinity in nanomolar concentrations with both PRMT5-MEP50 than EZH2. Further in vitro methylation and cell-based assays proved the inhibitory potential of EGCG by reducing the catalytic products of PRMT5 and EZH2 i.e., H4R3me2s & H3K27me3 respectively and showed that it induced autophagy and apoptosis. Furthermorein vivo, mouse xenografts studies demonstrated that oral dosage, reduced tumor size significantly with reduction in proliferation marker Ki67 and these histone repressive marks. Finally conclude that inhibition of PRMT5 and EZH2 by EGCG potentially can be used to develop combined therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Nalla,

Chatterjee,

Poyya

et al. 2024

Preprint

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“…Mutations affecting PRC2 activity, such as gain-of-function, hypomorph, and loss-of-function mutations in genes encoding the core components, are widespread in cancer ( 56 ). Several PRC2 inhibitors were shown to impair the proliferation of cultured cancer cells and are now in clinical trials ( 57 ). Lowering PRC2 activity is expected to alter the balance between methylation of H3K27 and the influx of unmodified histone molecules.…”

Section: Discussionmentioning

confidence: 99%

Forecasting histone methylation by Polycomb complexes with minute-scale precision

Lundkvist,

Lizana,

Schwartz

2023

Sci. Adv.

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Animals use the Polycomb system to epigenetically repress developmental genes. The repression requires trimethylation of lysine 27 of histone H3 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2), but the dynamics of this process is poorly understood. To bridge the gap, we developed a computational model that forecasts H3K27 methylation in Drosophila with high temporal resolution and spatial accuracy of contemporary experimental techniques. Using this model, we show that pools of methylated H3K27 in dividing cells are defined by the effective concentration of PRC2 and the replication frequency. We find that the allosteric stimulation by preexisting H3K27me3 makes PRC2 better in methylating developmental genes as opposed to indiscriminate methylation throughout the genome. Applied to Drosophila development, our model argues that, in this organism, the intergenerationally inherited H3K27me3 does not “survive” rapid cycles of embryonic chromatin replication and is unlikely to transmit the memory of epigenetic repression to the offspring. Our model is adaptable to other organisms, including mice and humans.

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“… 499 The administration of the lysine inhibitors tazemetostat, SHR2554, and pinometostat exhibited satisfactory therapeutic efficacy in several cancers with an acceptable safety profile. 500 Further studies are still required to explore possible avenues for targeting metabolic memory in combination with cancer treatment.…”

Section: Prospects For Metabolic Memory Applicationsmentioning

confidence: 99%

Metabolic memory: mechanisms and diseases

Dong,

Sun,

Nie

et al. 2024

Sig Transduct Target Ther

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Metabolic diseases and their complications impose health and economic burdens worldwide. Evidence from past experimental studies and clinical trials suggests our body may have the ability to remember the past metabolic environment, such as hyperglycemia or hyperlipidemia, thus leading to chronic inflammatory disorders and other diseases even after the elimination of these metabolic environments. The long-term effects of that aberrant metabolism on the body have been summarized as metabolic memory and are found to assume a crucial role in states of health and disease. Multiple molecular mechanisms collectively participate in metabolic memory management, resulting in different cellular alterations as well as tissue and organ dysfunctions, culminating in disease progression and even affecting offspring. The elucidation and expansion of the concept of metabolic memory provides more comprehensive insight into pathogenic mechanisms underlying metabolic diseases and complications and promises to be a new target in disease detection and management. Here, we retrace the history of relevant research on metabolic memory and summarize its salient characteristics. We provide a detailed discussion of the mechanisms by which metabolic memory may be involved in disease development at molecular, cellular, and organ levels, with emphasis on the impact of epigenetic modulations. Finally, we present some of the pivotal findings arguing in favor of targeting metabolic memory to develop therapeutic strategies for metabolic diseases and provide the latest reflections on the consequences of metabolic memory as well as their implications for human health and diseases.

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Use of histone methyltransferase inhibitors in cancer treatment: A systematic review

Cited by 19 publications

References 52 publications

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Forecasting histone methylation by Polycomb complexes with minute-scale precision

Metabolic memory: mechanisms and diseases

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