Small molecules targeting selected histone methyltransferases (HMTs) for cancer treatment: Current progress and novel strategies

Li, Deping; Peng, Xiaopeng; Hu, Zhihao; Li, Shuqing; Chen, Jianjun; Pan, Wanyi

doi:10.1016/j.ejmech.2023.115982

Cited by 6 publications

(8 citation statements)

References 156 publications

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Section: Introductionmentioning

confidence: 99%

“…Histone methyltransferases (HMTs) are selectively catalyze the methylation of lysine or arginine residues of target histone or non-histone proteins, and classified as lysine methyltransferases (KMTs) and arginine methyltransferases (PRMTs) respectively. The KMTs are in two families: containing SET domain KMTs, which include Trithorax, Enhancer of Zeste (EZH), Su(var)3-9, and non-SET domain-containing KMTs, like DOT1-like proteins (4) . The EZH1, and EZH2 are two well-known methyltransferases among KMTs.…”

Section: Introductionmentioning

confidence: 99%

“…The mechanism of upregulation of PRMT5 in disease status is still unknown. Interestingly recently studies reported that the functional association of both PRMT5 and EZH2 and it has been targeted for combined therapy (4,8) . Considering fact that PRMT5 and EZH2 are involved in a wide range of physiological processes, and are crucial for the maintenance of cancer phenotypes, and perturbation of PRMT5 and EZH2 may be a novel strategy.…”

Section: Introductionmentioning

confidence: 99%

“…The methyltransferases being dependent on the cofactor (methyl group donor) SAM or AdoMet were targeted with SAM-analogue compounds or structural derivatives, mostly of synthetic origin (40) . Many researchers are targeting to find the small molecular inhibitors to develop inhibitors against PRMT5 (4,10,14) . EZH2 (4, 8,9) .…”

Section: Introductionmentioning

confidence: 99%

“…Many researchers are targeting to find the small molecular inhibitors to develop inhibitors against PRMT5 (4,10,14) . EZH2 (4, 8,9) . A large number of selective SAM-competitive inhibitors of EZH2 have been developed to inhibit both the wild and mutant form of EZH2 (39,41) .…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

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Dual-target EZH2 inhibitor: latest advances in medicinal chemistry

Wei,

Mei,

et al. 2024

Future Medicinal Chemistry

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PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer

Liu,

Li,

et al. 2024

Mol Cancer

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Background Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. Methods This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. Results Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). Conclusions Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.

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Small molecules targeting selected histone methyltransferases (HMTs) for cancer treatment: Current progress and novel strategies

Cited by 6 publications

References 156 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

Dual-target EZH2 inhibitor: latest advances in medicinal chemistry

PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer

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