SETDB1

What is SETDB1 protein?

SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) gene is a protein coding gene which situated on the long arm of chromosome 1 at locus 1q21. SETDB1 protein is a protein-coding gene that functions as a histone methyltransferase. It is a prominent member of the Suppressor of Variegation 3-9 (SUV39)-related protein lysine methyltransferases (PKMTs) and is involved in methylating Histone 3 lysine 9 (H3K9) residues. This methylation promotes chromatin compaction and exerts negative regulation on gene expression. SETDB1 plays a central role in normal physiology and nervous system development, and it has been implicated in various cellular processes such as cell cycle progression, X chromosome inactivation, immune cell function, and the formation of promyelocytic leukemia (PML) nuclear bodies. The SETDB1 protein is consisted of 1291 amino acids and its molecular mass is approximately 143.2 kDa.

What is the function of SETDB1 protein?

SETDB1 promotes chromatin condensation and inhibits gene expression by catalyzing the methylation of the 9th lysine residue (H3K9) of histone H3. This methylation is associated with transcriptional inhibition and is essential for maintaining a stable intracellular environment and responding to external changes. SETDB1 plays a central role in normal physiology and nervous system development, and is involved in the regulation of a variety of cellular processes, including cell cycle regulation, X chromosome inactivation, immune cell function, endogenous retrovirus (ERV) expression, and nucleosome formation in promyelocytic leukemia (PML). The function of SETDB1 is not limited to the methylation of histone proteins, it is also involved in the regulation of a variety of biological processes and diseases by methylating non-histone proteins, such as aging, tumors, and inflammatory bowel disease (IBD). The function and molecular mechanisms of SETDB1 have important research and therapeutic potential in cell fate determination, stem cells, and tumors and other diseases.

Fig1. SETDB1 systematically regulates transcription and expression of cytokines, lymphocytes, proteins, and transposable elements in cancerous cells. (Eleanor Johnson, 2023)

SETDB1 Related Signaling Pathway

SETDB1 is a specific histone methyltransferase capable of trimethylating the 9th lysine residue of histone H3 (H3K9me3), an epigenetic mark associated with transcriptional suppression. SETDB1 may regulate the development of certain cancers, including colorectal cancer, through the Wnt/β-catenin signaling pathway. SETDB1 plays a role in gene silencing by mediating H3K9me3, which interacts with heterochromatin protein 1 (HP1) and promotes conformational transition from euchromatin to heterochromatin. SETDB1 is involved in regulating the expression of cell cycle-related genes, influencing cell cycle progression and cell aging, for example by affecting the expression of BMI1 and c-myc.

SETDB1 Related Diseases

SETDB1 has been found to be deregulated in carcinogenesis and is associated with the pathogenesis of several types of cancer, including gliomas, SETDB1 melanoma, and tumors of the lung, breast, gastrointestinal, and ovarian regions, where it often plays an oncogenic role. SETDB1's aberrant activity is also implicated in neuropsychiatric, cardiovascular, and gastrointestinal diseases, such as schizophrenia, Huntington's disease, congenital heart defects, and inflammatory bowel disease. The unique structural and biochemical features of SETDB1 contribute to its regulation and its molecular and cellular impact in both normal physiology and disease, with potential therapeutic implications.

Bioapplications of SETDB1

Abnormal activity of SETDB1 has been linked to the development of a variety of SETDB1 cancers and is therefore a potential drug target. By developing small molecule drugs like SETDB1 inhibitor or SETDB1 antibody, it may be helpful to treat related cancers. Abnormal expression of SETDB1 in some cancers may serve as a marker for diagnosis and prognosis, helping physicians assess disease status and response to treatment. SETDB1 protein and its related antibodies can be used as research tools to explore intracellular signaling pathways, protein interaction networks, and cell cycle regulation.

Case Study 1: Wenlin Yang, 2024

SET domain bifurcated 1 (SETDB1), a pivotal histone lysine methyltransferase, is transported to the cytoplasm via a chromosome region maintenance 1 (CMR1)‑dependent pathway, contributing to non‑histone methylation. However, the function and underlying mechanism of cytoplasmic SETDB1 in breast cancer remain elusive. In the present study, immunohistochemistry revealed that elevated cytoplasmic SETDB1 was correlated with lymph node metastasis and more aggressive breast cancer subtypes. Functionally, wound healing and Transwell assays showed that cytoplasmic SETDB1 is key for cell migration and invasion, as well as induction of epithelial‑mesenchymal transition (EMT), which was reversed by leptomycin B (LMB, a CMR1 inhibitor) treatment. Furthermore, RNA‑seq and metabolite detection revealed that cytoplasmic SETDB1 was associated with metabolism pathway and elevated levels of metabolites involved in the Warburg effect, including glucose, pyruvate, lactate and ATP. Immunoblotting and reverse transcription‑quantitative PCR verified that elevation of cytoplasmic SETDB1 contributed to elevation of c‑MYC expression and subsequent upregulation of lactate dehydrogenase A (LDHA) expression. Notably, gain‑ and loss‑of‑function approaches revealed that LDHA overexpression in T47D cells enhanced migration and invasion by inducing EMT, while its depletion in SETDB1‑overexpressing MCF7 cells reversed SETDB1‑induced migration and invasion, as well as the Warburg effect and EMT.

Fig1. Representative immunofluorescence of exogenous SETDB1 (red) localization in MCF7 cells.

Fig2. Metabolite levels in SETDB1-deficient BT549.

Case Study 2: Xiaowei She, 2023

MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post-transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post-translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip-mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri-methylation promotes tumor glycolysis and M2-like polarization of tumor-associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri-methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1-mediated tri-methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC.

Fig3. In vitro binding assay was performed.

Fig4. In vitro methylation assay was performed.

SETDB1 has several biochemical functions, for example, DNA binding,histone-lysine N-methyltransferase activity,protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by SETDB1 itself. We selected most functions SETDB1 had, and list some proteins which have the same functions with SETDB1. You can find most of the proteins on our site.

SETDB1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with SETDB1 here. Most of them are supplied by our site. Hope this information will be useful for your research of SETDB1.

AKT1;DNMT3A;MBD1;TTR