SMYD5

Last update 23 Jan 2025

Basic Info

Synonyms

[histone H4]-lysine20 N-trimethyltransferase SMYD5, Histone-lysine N-trimethyltransferase SMYD5, NN8-4AG

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Introduction

Histone methyltransferase that specifically trimethylates 'Lys-20' of histone H4 to form trimethylated histone H4 lysine 20 (H4K20me3) which represents a specific tag for epigenetic transcriptional repression (By similarity). In association with the NCoR corepressor complex, is involved in the repression of toll-like receptor 4 (TLR4)-target inflammatory genes in macrophages by catalyzing the formation of H4K20me3 at the gene promoters (By similarity). Plays an important role in embryonic stem (ES) cell self-renewal and differentiation (By similarity). Promotes ES cell maintenance by silencing differentiation genes through deposition of H4K20me3 marks (By similarity). Maintains genome stability of ES cells during differentiation through regulation of heterochromatin formation and repression of endogenous repetitive DNA elements by depositing H4K20me3 marks (PubMed:28951459).

100 Clinical Results associated with SMYD5

100 Translational Medicine associated with SMYD5

0 Patents (Medical) associated with SMYD5

Literatures (Medical) associated with SMYD5

15 Aug 2024·Nature

SMYD5 methylation of rpL40 links ribosomal output to gastric cancer

Article

Author: Garcia, Benjamin A ; Jovanovic, Predrag ; Ajani, Jaffer A ; Szkop, Krzysztof J ; Benitez, Ana Morales ; Francis, Joel W ; Larsson, Ola ; Husmann, Dylan ; Song, Shumei ; Jeong, Jinho ; Topisirovic, Ivan ; Zahn, Emily ; Chen, Ying-Jiun C ; Wang, Linghua ; Singh, Kamini ; Gozani, Or ; Flores, Natasha M ; Mazur, Pawel K ; Wu, Jibo ; Park, Juhyung

Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis^1,2. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites. A biochemical-proteomics strategy identifies the monoubiquitin fusion protein partner rpL40 (ref. ³) as the principal physiological substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprogrammes protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in samples from patients with GAC and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease, including peritoneal carcinomatosis. Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to inhibitors of PI3K and mTOR. Finally, combining SMYD5 depletion with PI3K-mTOR inhibition and chimeric antigen receptor T cell administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived peritoneal carcinomatosis. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates the evolution of malignant GAC and proposes SMYD5 targeting as part of a potential combination therapy to treat this cancer.

01 Aug 2024·Cell Reports

SMYD5 is a regulator of the mild hypothermia response

Article

Author: Ostacolo, Kevin ; Halldorsdottir, Sara Tholl ; Reynisdottir, Tinna ; Rafnsdottir, Salvor ; Möller, Katrin ; Zhang, Li ; Jang, Kijin ; Vinod, Meghna ; Anderson, Kimberley Jade ; Allison, Kristin Elisabet ; Halldorsdottir, Katrin ; Tomasdottir, Arnhildur ; Atladottir, Laufey Halla ; Chavez-Valdez, Raul ; Magnusdottir, Erna ; Bjornsson, Hans Tomas ; He, Jin ; Northington, Frances J

The mild hypothermia response (MHR) maintains organismal homeostasis during cold exposure and is thought to be critical for the neuroprotection documented with therapeutic hypothermia. To date, little is known about the transcriptional regulation of the MHR. We utilize a forward CRISPR-Cas9 mutagenesis screen to identify the histone lysine methyltransferase SMYD5 as a regulator of the MHR. SMYD5 represses the key MHR gene SP1 at euthermia. This repression correlates with temperature-dependent levels of histone H3 lysine 26 trimethylation (H3K36me3) at the SP1 locus and globally, indicating that the mammalian MHR is regulated at the level of histone modifications. We have identified 37 additional SMYD5-regulated temperature-dependent genes, suggesting a broader MHR-related role for SMYD5. Our study provides an example of how histone modifications integrate environmental cues into the genetic circuitry of mammalian cells and provides insights that may yield therapeutic avenues for neuroprotection after catastrophic events.

01 May 2024·Molecules and Cells

Negative regulation of SH2B3 by SMYD5 controls epithelial-mesenchymal transition in lung cancer

Article

Author: Lee, Jeong Min ; Lee, Jinkwon ; Ko, Jung Heon ; Kim, Dae-Soo ; Kang, Yunsang ; Kim, Kwanho ; Ryu, Tae Young ; Cho, Hyun-Soo ; Tae, In Hwan ; Kim, Hee-Won ; Son, Mi-Young

The main cause of death in lung cancer patients is metastasis. Thus, efforts to suppress micrometastasis or distant metastasis in lung cancer, identify therapeutic targets and develop related drugs are ongoing. In this study, we identified SET and MYND domain-containing protein 5 (SMYD5) as a novel metastasis regulator in lung cancer and found that SMYD5 was overexpressed in lung cancer based on both RNA-sequencing analysis results derived from the TCGA portal and immunohistochemical analysis results; knockdown of SMYD5 inhibited cell migration and invasion by changing epithelial-mesenchymal transition markers and MMP9 expression in NCI-H1299 and H1703 cell lines. Additionally, SMYD5 knockdown increased Src homology 2-b3 expression by decreasing the level of H4K20 trimethylation. Furthermore, in an in vitro epithelial-mesenchymal transition system using TGF-β treatment, SMYD5 knockdown resulted in reduced cell migration and invasion in the highly invasive NCI-H1299 and H1703 cell lines. Based on these findings, we propose that SMYD5 could serve as a potential therapeutic target for lung cancer treatment and that cotreatment with an SMYD5 inhibitor and chemotherapy may enhance the therapeutic effect of lung cancer treatment.

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SMYD5

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