The SMYD family proteins in immunology: An update of their obvious and non-obvious relations with the immune system

Rubio-Tomás, Teresa

doi:10.1016/j.heliyon.2021.e07387

Cited by 6 publications

(13 citation statements)

References 42 publications

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“…The SYMD3 SET domain supported the trimethylation of H3K4, H4K5, and H4K20. These, in turn, managed transcriptional control by interacting with an RNA polymerase complex [ 3 , 31 ]. This type of enzymatic histone alteration was augmented by tumor-specific proteolysis of the SMYD3 N-terminal 34 residues to release the methylated protein substrate [ 31 ].…”

Section: Smyd-proteins Structure Function and Medicinal Potentialmentioning

confidence: 99%

“…Since then, SMYD3 has been linked to the tumorigenic cascade for various types of cancer in which methyltransferase activity is dysregulated [ 30 , 31 , 113 ]. SMYD3 is overexpressed in hepatocellular carcinomas and colorectal carcinomas and contributes to the proliferation of breast carcinoma cells [ 3 , 30 , 31 ]. In the presence of overexpressed SMYD3, there have been 80 genes detected that exhibit altered gene expression.…”

Section: Smyd-proteins Structure Function and Medicinal Potentialmentioning

confidence: 99%

“…SMYDs are a family of five unique lysine methyltransferases (PKMTs) that catalyze the transfer of donor methyl groups from S-adenosylmethionine (SAM) to specific lysines on histones and non-histone substrates [ 1 , 2 , 3 , 4 , 5 , 6 ]. The resulting changes in chromatin structure and altered transcriptional regulation can lead to diseases or be associated with poorer outcomes for specific cancers [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. SMYD proteins contain both functional SET (suppressor of variegation, enhancer of zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domains ( Figure 1 ) [ 1 , 2 , 6 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Some SMYDs are found only in cancerous cells, representing potential targets for pharmacologic agents, while others have been identified in both healthy and cancerous tissues. Because SMYD proteins play a role in gene expression regulation in host immunity against pathogen infection, hematopoiesis, and several cancers, there are obvious and less obvious relationships between SMYDs and immune system function [ 3 ]. SMYD overexpression can be linked to several diseases.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases

et al. 2023

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A comprehensive understanding of the mechanisms involved in epigenetic changes in gene expression is essential to the clinical management of diseases linked to the SMYD family of lysine methyltransferases. The five known SMYD enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine (SAM) to specific lysines on histones and non-histone substrates. SMYDs family members have distinct tissue distributions and tissue-specific functions, including regulation of development, cell differentiation, and embryogenesis. Diseases associated with SMYDs include the repressed transcription of SMYD1 genes needed for the formation of ion channels in the heart leading to heart failure, SMYD2 overexpression in esophageal squamous cell carcinoma (ESCC) or p53-related cancers, and poor prognosis associated with SMYD3 overexpression in more than 14 types of cancer including breast cancer, colon cancer, prostate cancer, lung cancer, and pancreatic cancer. Given the importance of epigenetics in various pathologies, the development of epigenetic inhibitors has attracted considerable attention from the pharmaceutical industry. The pharmacologic development of the inhibitors involves the identification of molecules regulating both functional SMYD SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domains, a process facilitated by available X-ray structures for SMYD1, SMYD2, and SMYD3. Important leads for potential pharmaceutical agents have been reported for SMYD2 and SMYD3 enzymes, and six epigenetic inhibitors have been developed for drugs used to treat myelodysplastic syndrome (Vidaza, Dacogen), cutaneous T-cell lymphoma (Zoinza, Isrodax), and peripheral T-cell lymphoma (Beleodag, Epidaza). The recently demonstrated reversal of SMYD histone methylation suggests that reversing the epigenetic effects of SMYDs in cancerous tissues may be a desirable target for pharmacological development.

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Section: Smyd-proteins Structure Function and Medicinal Potentialmentioning

confidence: 99%

Section: Smyd-proteins Structure Function and Medicinal Potentialmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases

et al. 2023

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“…Two hours after TLR4-mediated activation, down-regulation of PHF2 resulted in an increase in the inflammatory promoter H4K20me3, and a decrease in the activation of inflammatory genes such as TNF-α and CXCL10 ( 124 ). In addition, SMYD2 specifically facilitates H3K36 di-methylation on the IL-6 supporters, thus suppressing the production of pro-inflammatory cytokines induced by macrophage activation ( 125 ).…”

Section: Histone Modification and Innate Immunitymentioning

confidence: 99%

Histones: The critical players in innate immunity

Peng

et al. 2022

Front. Immunol.

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The highly conserved histones in different species seem to represent a very ancient and universal innate host defense system against microorganisms in the biological world. Histones are the essential part of nuclear matter and act as a control switch for DNA transcription. However, histones are also found in the cytoplasm, cell membranes, and extracellular fluid, where they function as host defenses and promote inflammatory responses. In some cases, extracellular histones can act as damage-associated molecular patterns (DAMPs) and bind to pattern recognition receptors (PRRs), thereby triggering innate immune responses and causing initial organ damage. Histones and their fragments serve as antimicrobial peptides (AMPs) to directly eliminate bacteria, viruses, fungi, and parasites in vitro and in vivo. Histones are also involved in phagocytes-related innate immune response as components of neutrophil extracellular traps (NETs), neutrophil activators, and plasminogen receptors. In addition, as a considerable part of epigenetic regulation, histone modifications play a vital role in regulating the innate immune response and expression of corresponding defense genes. Here, we review the regulatory role of histones in innate immune response, which provides a new strategy for the development of antibiotics and the use of histones as therapeutic targets for inflammatory diseases, sepsis, autoimmune diseases, and COVID-19.

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