Exploring the epigenetic drug discovery landscape

Prachayasittikul, Veda; Prathipati, Philip; Pratiwi, Reny; Phanus‐umporn, Chuleeporn; Malik, Aijaz Ahmad; Schaduangrat, Nalini; Seenprachawong, Kanokwan; Wongchitrat, Prapimpun; Supokawej, Aungkura; Prachayasittikul, Virapong; Wikberg, Jarl E. S.; Nantasenamat, Chanin

doi:10.1080/17460441.2017.1295954

Cited by 64 publications

(41 citation statements)

References 96 publications

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“…Epigenetics has been widely illuminated in multiple diseases over the past decades, and researchers are consistently seeking for new remedy from this field ( Prachayasittikul et al, 2017 ). Currently, a diverse set of RNA modifications has been identified and annotated.…”

Section: Discussionmentioning

confidence: 99%

Multifaceted Functions and Novel Insight Into the Regulatory Role of RNA N6-Methyladenosine Modification in Musculoskeletal Disorders

Zhang

Liu

et al. 2020

Front. Cell Dev. Biol.

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RNA modifications have emerged as key regulators of transcript expression in diverse physiological and pathological processes. As one of the most prevalent types of RNA modifications, N 6 -methyladenosine (m 6 A) has become the highlight in modulation of various diseases through interfering RNA splicing, translation, nuclear export, and decay. In many cases, the detailed functions of m 6 A in cellular processes and diseases remain unclear. Notably, recent studies have determined the relationship between m 6 A modification and musculoskeletal disorders containing osteosarcoma, osteoarthritis, rheumatoid arthritis, osteoporosis, etc. Herein, this review comprehensively summarizes the recent advances of m 6 A modification in pathogenesis and progression of musculoskeletal diseases. Specifically, the underlying molecular mechanisms, detection technologies, regulatory functions, clinical implications, and future perspectives of m 6 A in musculoskeletal disorders are discussed, with the aim to provide a novel insight into their association.

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Section: Discussionmentioning

confidence: 99%

Multifaceted Functions and Novel Insight Into the Regulatory Role of RNA N6-Methyladenosine Modification in Musculoskeletal Disorders

Zhang

Liu

et al. 2020

Front. Cell Dev. Biol.

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“…These treatment types were separately analyzed for all tumor entities in order find out which approaches would be most promising in specific entities in the future. To quantify developments in basic and translational cancer research, we included a wide range of topics such as the combination of immunotherapy with stroma 10 and cancer-associated fibroblasts, 11 angiogenesis, 12 tumor-specific antigens, 13 neoantigens, 14 microbiota, 15 drug resistance, 16 myeloid cells, 17 stem cells, 18 epigenetics, 19 cell death and autophagy 20 , 21 as well as metabolism. 22 All trends were analyzed over time, keeping in mind that the field was profoundly changed by landmark events such as the first clinical report of effective checkpoint inhibition in cancer patients in 2003.…”

Section: Introductionmentioning

confidence: 99%

Large-scale database mining reveals hidden trends and future directions for cancer immunotherapy

et al. 2018

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Cancer immunotherapy has fundamentally changed the landscape of oncology in recent years and significant resources are invested into immunotherapy research. It is in the interests of researchers and clinicians to identify promising and less promising trends in this field in order to rationally allocate resources. This requires a quantitative large-scale analysis of cancer immunotherapy related databases.We developed a novel tool for text mining, statistical analysis and data visualization of scientific literature data. We used this tool to analyze 72002 cancer immunotherapy publications and 1469 clinical trials from public databases. All source codes are available under an open access license.The contribution of specific topics within the cancer immunotherapy field has markedly shifted over the years. We show that the focus is moving from cell-based therapy and vaccination towards checkpoint inhibitors, with these trends reaching statistical significance. Rapidly growing subfields include the combination of chemotherapy with checkpoint blockade. Translational studies have shifted from hematological and skin neoplasms to gastrointestinal and lung cancer and from tumor antigens and angiogenesis to tumor stroma and apoptosis.This work highlights the importance of unbiased large-scale database mining to assess trends in cancer research and cancer immunotherapy in particular. Researchers, clinicians and funding agencies should be aware of quantitative trends in the immunotherapy field, allocate resources to the most promising areas and find new approaches for currently immature topics.

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“…These advances improve our understanding of cholangiocyte pathobiology and periportal scar formation and should allow for the optimization of future antifibrotic protocols. This is particularly appealing in the era of epigenetic pharmacology, an approach that is already reaching clinical trials for various diseases and allowing for better precision in molecular targeting …”

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confidence: 99%

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

et al. 2019

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During biliary disease, cholangiocytes become activated by various pathological stimuli, including transforming growth factor β (TGF-β). The result is an epigenetically regulated transcriptional program leading to a pro-fibrogenic microenvironment, activation of hepatic stellate cells (HSCs), and progression of biliary fibrosis. This study evaluated how TGF-β signaling intersects with epigenetic machinery in cholangiocytes to support fibrogenic gene transcription. We performed RNA sequencing in cholangiocytes with or without TGF-β. Ingenuity pathway analysis identified "HSC Activation" as the highly up-regulated pathway, including overexpression of fibronectin 1 (FN), connective tissue growth factor, and other genes. Bioinformatics identified enhancer of zeste homologue 2 (EZH2) as an epigenetic regulator of the cholangiocyte TGF-β response. EZH2 overexpression suppressed TGF-β-induced FN protein in vitro, suggesting FN as a direct target of EZH2-based repression. Chromatin immunoprecipitation assays identified an FN promoter element in which EZH2-mediated tri-methylation of lysine 27 on histone 3 is diminished by TGF-β. TGF-β also caused a 50% reduction in EZH2 protein levels. Proteasome inhibition rescued EZH2 protein and led to reduced FN production. Immunoprecipitation followed by mass spectrometry identified ubiquitin protein ligase E3 component N-recognin 4 in complex with EZH2, which was validated by western blotting in vitro. Ubiquitin mutation studies suggested K63-based ubiquitin linkage and chain elongation on EZH2 in response to TGF-β. A deletion mutant of EZH2, lacking its N-terminal domain, abrogates both TGF-β-stimulated EZH2 degradation and FN release. In vivo, cholangiocyte-selective knockout of EZH2 exacerbates bile duct ligation-induced fibrosis whereas MDR2 -/mice are protected from fibrosis by the proteasome inhibitor bortezomib. Conclusion: TGF-β regulates proteasomal degradation of EZH2 through N-terminal, K63-linked ubiquitination in cholangiocytes and activates transcription of a fibrogenic gene program that supports biliary fibrosis.

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Exploring the epigenetic drug discovery landscape

Cited by 64 publications

References 96 publications

Multifaceted Functions and Novel Insight Into the Regulatory Role of RNA N6-Methyladenosine Modification in Musculoskeletal Disorders

Multifaceted Functions and Novel Insight Into the Regulatory Role of RNA N6-Methyladenosine Modification in Musculoskeletal Disorders

Large-scale database mining reveals hidden trends and future directions for cancer immunotherapy

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

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