SETD7 functions as a transcription repressor in prostate cancer via methylating FOXA1.

Dysregulation of histone lysine methyltransferases and demethylases is one of the major mechanisms driving the epigenetic reprogramming of transcriptional networks in castration-resistant prostate cancer (CRPC). In addition to their canonical histone targets, some of these factors can modify critical transcription factors, further impacting oncogenic transcription programs. Our recent report demonstrated that LSD1 can demethylate the lysine 270 of FOXA1 in prostate cancer (PCa) cells, leading to the stabilization of FOXA1 chromatin binding. This process enhances the activities of the androgen receptor and other transcription factors that rely on FOXA1 as a pioneer factor. However, the identity of the methyltransferase responsible for FOXA1 methylation and negative regulation of the FOXA1-LSD1 oncogenic axis remains unknown. SETD7 was initially identified as a transcriptional activator through its methylation of histone 3 lysine 4, but its function as a methyltransferase on nonhistone substrates remains poorly understood, particularly in the context of PCa progression. In this study, we reveal that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as the major methyltransferase targeting FOXA1-K270. This methylation disrupts FOXA1-mediated transcription. Consistent with its molecular function, we found that SETD7 confers tumor suppressor activity in PCa cells. Moreover, loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Overall, our study provides mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.

Methyltransferase Set7/9 controls PARP1 expression and regulates cisplatin response of breast cancer cells.

The protein-specific methyltransferase Set7/9 is known for its ability to add methyl groups to lysine residues on many targets, including as histones H1.4, H2A, H2B, H3, and non-histone proteins such as p53, NFκB, E2F1, pRb, Hif1α, ß-catenin, STAT3, and YY1 transcription factors. Set7/9 affects both the landscape of histone modifications and the functionality of the aforementioned TFs, and acts as an essential mediator of vital cellular functions, regulating tumor growth and the neoplastic transformation of normal cells. The number of studies demonstrating the determining role of Set7/9 in cancer is growing. Importantly, the effect of Set7/9 on tumor progression is ambivalent and cancer-type dependent. In this study we analyzed the potential participation of Set7/9 in the essential cellular processes in breast cancer cells and revealed that Set7/9 may be involved in DNA damage signaling and DNA repair processes. We further demonstrated that Set7/9 expression is downregulated in cancerous breast tissues and inversely correlated to PARP1 expression level. Using breast cancer cell lines of HER2-positive and triple negative subtypes we have shown that the attenuation of Set7/9 led to the stabilization of PARP1 on both mRNA and protein levels that in turn resulted in cisplatin resistance acquiring. Finally, we demonstrated that the combination of cisplatin with FDA approved PARP1 inhibitor niraparib (Zejula) has a synergistic effect with cisplatin and thereby allows to overcome cisplatin resistance of Set7/9 deficient breast cancer cells.

Unravelling the molecular mechanistic pathway underlying the anticancer effects of kaempferol in colorectal cancer: a reverse pharmacology network approach.

Colorectal cancer (CRC) is the third most diagnosed and highly fatal malignancy, presenting serious health concerns worldwide. The search for an effective cure for CRC is challenging and poses a serious concern. Kaempferol is a potent anti-cancerous bioactive compound often suggested for treating various cancers, including CRC. However, its underlying molecular mechanism against CRC remains unclear. The present study delves into kaempferol's molecular pathways and underlying molecular mechanisms against CRC targets. The target protein-coding genes for kaempferol were retrieved, and the CRC-associated genes were curated. Twelve common targets with a disease specificity index of > 0.6 were validated for their protein expression at different stages of CRC. Over-expressed USP1, SETD7, POLH, TDP1 and RACGAP1 were selected for further studies. The binding affinities of kaempferol to the corresponding proteins were evaluated using molecular docking and Molecular Dynamics (MD) simulations. SETD7 exhibited the highest binding affinity with the lowest binding energy (- 8.06 kcal/mol). Additionally, the MD simulation, and MM-PBSA conferred SETD7-kaempferol complex had the least root-mean-square deviation with lower interaction energy and higher conformational stability. The protein-protein interaction of SETD7 constructed revealed direct interactors, namely, DNMT1, FOXO1, FOXO3, FOXO4, H3-3B, H3-4, H3C12, H3C13, SETD7, SIRT1 and TP53, have a potential role in cancer progression through FOXO signalling. In summary, our study revealed kaempferol's multi-target and synergistic effect on multiple CRC targets and its underlying mechanisms. Finally, the study recommends in-vitro and in-vivo trials for validation of anti-cancerous drugs for CRC.

Lysine Methylation-Dependent Proteolysis by the Malignant Brain Tumor (MBT) Domain Proteins.

Lysine methylation is a major post-translational protein modification that occurs in both histones and non-histone proteins. Emerging studies show that the methylated lysine residues in non-histone proteins provide a proteolytic signal for ubiquitin-dependent proteolysis. The SET7 (SETD7) methyltransferase specifically transfers a methyl group from S-Adenosyl methionine to a specific lysine residue located in a methylation degron motif of a protein substrate to mark the methylated protein for ubiquitin-dependent proteolysis. LSD1 (Kdm1a) serves as a demethylase to dynamically remove the methyl group from the modified protein. The methylated lysine residue is specifically recognized by L3MBTL3, a methyl-lysine reader that contains the malignant brain tumor domain, to target the methylated proteins for proteolysis by the CRL4DCAF5 ubiquitin ligase complex. The methylated lysine residues are also recognized by PHF20L1 to protect the methylated proteins from proteolysis. The lysine methylation-mediated proteolysis regulates embryonic development, maintains pluripotency and self-renewal of embryonic stem cells and other stem cells such as neural stem cells and hematopoietic stem cells, and controls other biological processes. Dysregulation of the lysine methylation-dependent proteolysis is associated with various diseases, including cancers. Characterization of lysine methylation should reveal novel insights into how development and related diseases are regulated.

SLCO4A1-AS1 regulates laryngeal squamous cell carcinoma cell phenotypes via the Wnt pathway.

AIM: Long non-coding RNAs were widely reported to regulate laryngeal squamous cell carcinoma (LSCC), a prevalent tumor in the head and neck. We aimed to investigate the role of solute carrier organic anion transporter family member 4A1 antisense RNA 1 (SLCO4A1-AS1) in LSCC. MATERIALS & METHODS: CCK-8 and colony formation assays were conducted to examine the viability and proliferation of LSCC cells. The apoptosis of LSCC cells was evaluated using flow cytometry and TUNEL assays. The distribution of SLCO4A1-AS1 in LSCC cells was detected by subcellular fractionation assay. The interaction between molecules was confirmed using luciferase reporter assay. RESULTS: SLCO4A1-AS1 was overexpressed in LSCC tissues and cells. Furthermore, silenced SLCO4A1-AS1 repressed the proliferation and facilitated apoptosis of LSCC cells. Mechanistical investigation revealed that SLCO4A1-AS1 was a competing endogenous RNA (ceRNA) to upregulate SETD7 by binding with miR-7855-p. Additionally, SLCO4A1-AS1 positively regulated the Wnt/ß-catenin signaling pathway by upregulating SETD7. Rescue experiments demonstrated that SLCO4A1-AS1 promoted LSCC proliferation and inhibited LSCC apoptosis by upregulation of SETD7 and activation of the Wnt/ß-catenin pathway. CONCLUSION: SLCO4A1-AS1 promotes proliferation and inhibits apoptosis of LSCC cells by upregulation of SETD7 in a miR-7855-5p dependent way to activate the Wnt/ß-catenin pathway.

SetD7 (Set7/9) is a novel target of PPARγ that promotes the adaptive pancreatic ß-cell glycemic response.

Loss of functional pancreatic ß-cell mass leads to type 2 diabetes (T2D), attributable to modified ß-cell-dependent adaptive gene expression patterns. SetD7 is a histone methyltransferase enriched in pancreatic islets that mono- and dimethylates histone-3-lysine-4 (H3K4), promoting euchromatin modifications, and also maintains the regulation of key ß-cell function and survival genes. However, the transcriptional regulation of this important epigenetic modifier is unresolved. Here we identified the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARγ) as a major transcriptional regulator of SetD7 and provide evidence for direct binding and functionality of PPARγ in the SetD7 promoter region. Furthermore, constitutive shRNA-mediated PPARγ knockdown in INS-1 ß-cells or pancreas-specific PPARγ deletion in mice led to downregulation of SetD7 expression as well as its nuclear enrichment. The relevance of the SetD7-PPARγ interaction in ß-cell adaptation was tested in normoglycemic 60% partial pancreatectomy (Px) and hyperglycemic 90% Px rat models. Whereas a synergistic increase in islet PPARγ and SetD7 expression was observed upon glycemic adaptation post-60% Px, in hyperglycemic 90% Px rats, islet PPARγ, and PPARγ targets SetD7 and Pdx1 were downregulated. PPARγ agonist pioglitazone treatment in 90% Px rats partially restored glucose homeostasis and ß-cell mass and enhanced expression of SetD7 and Pdx1. Collectively, these data provide evidence that the SetD7-PPARγ interaction serves as an important element of the adaptive ß-cell response.

SETD7 mediates the vascular invasion in articular cartilage and chondrocytes apoptosis in osteoarthriis.

The pathological characteristics of osteoarthritis are cartilage matrix degradation, chondrocytes apoptosis, and low-grade inflammation of the joint. Recent studies have shown that blood vessels grow from the subchondral bone to the articular cartilage. However, the relationship among inflammation, angiogenesis, and chondrocyte apoptosis is still unclear. We found that chondrocytes could secrete chemokines and VEGF to promote the migration of vascular endothelial cells in response to TNF-α stimulation. The invasion of blood vessels leads to increased oxygen tension in the local environment, which increased the expression of SETD7 in chondrocytes by activating the JAK-STAT5 pathway. The bond of phosphorylated STAT5 and the specific locus in the promoter of SETD7 directly increased the transcription of SETD7. On the one hand, SETD7-regulated chemokine expression by forming a positive loop; on the other hand, SETD7-mediated chondrocyte apoptosis by inhibiting the nuclear localization of HIF-1α. In this study, we discovered a novel function of chondrocytes as mediators of inflammation and angiogenesis. Our study demonstrates that SETD7 is a potential molecular target to prevent OA development and progression.

Substrate docking-mediated specific and efficient lysine methylation by the SET domain-containing histone methyltransferase SETD7.

Lysine methylation of cellular proteins is catalyzed by dozens of lysine methyltransferases (KMTs), occurs in thousands of different histone and nonhistone proteins, and regulates diverse biological processes. Dysregulation of KMT-mediated lysine methylations underlies many human diseases. A key unanswered question is how proteins, nonhistone proteins in particular, are specifically methylated by each KMT. Here, using several biochemical approaches, including analytical gel filtration chromatography, isothermal titration calorimetry, and in vitro methylation assays, we discovered that SET domain-containing 7 histone lysine methyltransferase (SETD7), a KMT capable of methylating both histone and nonhistone proteins, uses its N-terminal membrane occupation and recognition nexus (MORN) repeats to dock its substrates and subsequently juxtapose their Lys methylation motif for efficient and specific methylation by the catalytic SET domain. Such docking site-mediated methylation mechanism rationalizes binding and methylation of previously known substrates and predicts new SETD7 substrates. Our findings further suggest that other KMTs may also use docking-mediated substrate recognition mechanisms to achieve their catalytic specificity and efficiency.

Long non-coding RNA LINC01194 promotes the proliferation, migration and invasion of lung adenocarcinoma cells by targeting miR-641/SETD7 axis.

BACKGROUND: It is increasingly evidenced that long non-coding RNAs (lncRNAs) play an important role in various diseases. LncRNA LINC01194 acts as an oncogene in several cancer types. Nevertheless, the role of LINC01194 in lung adenocarcinoma (LUAD) has not yet been revealed. METHODS: qRT-PCR was used to detect the expression of LINC01194, miR-641 and SETD7 mRNA, while western blot was exploited to examine SETD7 protein level. Cell proliferation was detected by colony formation and EdU assays. Transwell assays detected cell migration and invasion. TUNEL assay and flow cytometry analysis were used to detect cell apoptosis. RIP, RNA pull down and luciferase reporter assays detected the binding among LINC01194, miR-641 and SETD7. RESULTS: LINC01194 was significantly upregulated in LUAD tissues and cell lines. Knockdown of LINC01194 resulted in decreased cell proliferation, migration and invasion, and increased apoptosis. Mechanistic experiments unveiled that LINC01194 augmented SETD7 expression in LUAD cells by competitively interacting with miR-641. Rescue experiments showed that miR-641 inhibition and SETD7 overexpression rescued the repressing impacts on LUAD cell proliferation, migration and invasion caused by LINC01194 knockdown. CONCLUSION: LINC01194 promotes the progression of LUAD by enhancing miR-641-targeted SETD7. The LINC01194/miR-641/SETD7 axis might provide new molecular targets for treating LUAD.

The histone methyltransferase Setd7 promotes pancreatic progenitor identity.

Cell fate specification depends on transcriptional activation driven by lineage-specific transcription factors as well as changes in chromatin organization. To date, the interplay between transcription factors and chromatin modifiers during development is not well understood. We focus here on the initiation of the pancreatic program from multipotent endodermal progenitors. Transcription factors that play key roles in regulating pancreatic progenitor state have been identified, but the chromatin regulators that help to establish and maintain pancreatic fate are less well known. Using a comparative approach, we identify a crucial role for the histone methyltransferase Setd7 in establishing pancreatic cell identity. We show that Setd7 is expressed in the prospective pancreatic endoderm of Xenopus and mouse embryos prior to Pdx1 induction. Importantly, we demonstrate that setd7 is sufficient and required for pancreatic cell fate specification in Xenopus Functional and biochemical approaches in Xenopus and mouse endoderm support that Setd7 modulates methylation marks at pancreatic regulatory regions, possibly through interaction with the transcription factor Foxa2. Together, these results demonstrate that Setd7 acts as a central component of the transcription complex initiating the pancreatic program.

SETD7 mediates spinal microgliosis and neuropathic pain in a rat model of peripheral nerve injury.

Gene transcription regulation is critical for the development of spinal microgliosis and neuropathic pain after peripheral nerve injury. Using a model of chronic constriction injury (CCI) of the sciatic nerve, this study characterized the role of SET domain containing lysine methyltransferase 7 (SETD7) which monomethylates histone H3 lysine 4 (H3K4me1), a marker for active gene transcription. SETD7 protein expression in the spinal dorsal horn ipsilateral to nerve lesion was increased from one day to 14 days after CCI, concomitantly with the expression of inflammatory genes, Ccl2, Il-6 and Il-1ß. The CCI-induced SETD7 expression was predominantly localized to microglia, as demonstrated by immunohistochemistry and western blot from magnetic activated cell sorted spinal microglia. SETD7 knockdown by intrathecal lentivirus shRNA delivery prior to CCI prevented spinal microgliosis and neuropathic pain, whereas lentiviral SETD7 transduction exacerbated these symptoms. In addition, SETD7 regulated H3K4me1 level and expression of inflammatory mediators both in CCI rats and in the HAPI rat microglia cell line. Accordingly, PFI-2, a specific inhibitor of SETD7 monomethylation activity, suppressed the lipopolysaccharides-induced amoeboid morphology of primary microglia and the expression of inflammatory genes, Ccl2, Il-6 and Il-1ß. Moreover, intrathecal administration of PFI-2 alleviated CCI-induced neuropathic pain. However, this effect was observed in male but not in female rats. These results demonstrate a critical role of SETD7 in the development of spinal microgliosis and neuropathic pain subsequently to peripheral nerve injury. The pharmacological approach further suggests that SETD7 is a new target for the treatment of neuropathic pain. The underlying mechanisms may involve H3K4me1-dependent regulation of inflammatory gene expression in microglia.

Enhanced PKMT-substrate recognition through non active-site interactions.

Protein lysine methyltransferases (PKMTs) catalyze the methylation of lysine residues on many different cellular proteins. Despite extensive biochemical and structural studies, focusing on PKMT active site-peptide interactions, little is known regarding how PKMTs recognize globular substrates. To examine whether these enzymes recognize protein substrates through interactions that take place outside of the active site, we have measured SETD6 and SETD7 activity with both protein and peptide RelA substrate. We have utilized the MTase-Glo™ methyltransferase assay to measure the activity of SETD6 and SETD7 with the different RelA substrates and calculated the Michaelis-Menten (MM) parameters. We found an up to ∼12-fold increase in KM of the PKMTs activity with RelA peptide relative to the respective full-length protein, emphasizing the significantly higher PKMT-protein interaction affinity. Examination of SETD6 and SETD7 activity toward the same RelA substrates highlight the similarity in substrate recognition for both PKMTs. Our results show that the interaction affinity of SETD6 and SETD7 with RelA is enhanced through interactions that occur outside of the active site leading to higher catalytic efficiency and specificity. These interactions can significantly vary depending on the PKMT and the specific methylation site on RelA. Overall, our results underline that PKMTs can recognize their substrates through docking interactions that occur out of the active site-peptide region for enhancing their activity and specificity in the cellular environment.

Emerging roles of lysine methylation on non-histone proteins.

Lysine methylation is a common posttranslational modification (PTM) of histones that is important for the epigenetic regulation of transcription and chromatin in eukaryotes. Increasing evidence demonstrates that in addition to histones, lysine methylation also occurs on various non-histone proteins, especially transcription- and chromatin-regulating proteins. In this review, we will briefly describe the histone lysine methyltransferases (KMTs) that have a broad spectrum of non-histone substrates. We will use p53 and nuclear receptors, especially estrogen receptor alpha, as examples to discuss the dynamic nature of non-histone protein lysine methylation, the writers, erasers, and readers of these modifications, and the crosstalk between lysine methylation and other PTMs in regulating the functions of the modified proteins. Understanding the roles of lysine methylation in normal cells and during development will shed light on the complex biology of diseases associated with the dysregulation of lysine methylation on both histones and non-histone proteins.

SETD7 Promotes Cell Proliferation and Migration via Methylation-mediated TAF7 in Clear Cell Renal Cell Carcinoma.

SET domain containing 7(SETD7), a member of histone methyltransferases, is abnormally expressed in multiple tumor types. However, the biological function and underlying molecular mechanism of SETD7 in clear cell renal cell carcinoma (ccRCC) remain unclear. Here, we explored the biological effects of SETD7-TAF7-CCNA2 axis on proliferation and metastasis in ccRCC. We identified both SETD7 and TAF7 were up-regulated and significantly promoted the proliferation and migration of ccRCC cells. Concurrently, there was a significant positive correlation between the expression of SETD7 and TAF7, and the two were colocalized in the nucleus. Mechanistically, SETD7 methylates TAF7 at K5 and K300 sites, resulting in the deubiquitination and stabilization of TAF7. Furthermore, re-expression of TAF7 could partially restore SETD7 knockdown inhibited ccRCC cells proliferation and migration. In addition, TAF7 transcriptionally activated to drive the expression of cyclin A2 (CCNA2). And more importantly, the methylation of TAF7 at K5 and K300 sites exhibited higher transcriptional activity of CCNA2, which promotes formation and progression of ccRCC. Our findings reveal a unique mechanism that SETD7 mediated TAF7 methylation in regulating transcriptional activation of CCNA2 in ccRCC progression and provide a basis for developing effective therapeutic strategies by targeting members of SETD7-TAF7-CCNA2 axis.

The role of SET domain containing lysine methyltransferase 7 in tumorigenesis and development.

SET domain containing lysine methyltransferase 7 (SETD7) belongs to the protein lysine methyltransferase family and can catalyze the monomethylation of histone H3K4, which plays a vital role in the regulation of cell cycle, cell differentiation, DNA damage response and chromatin remodeling through K/R-S/T-K (K is lysine residue) sites and the recognition of substrates mediated by SET, i-SET, and n-SET domains and electrostatic action. SETD7 also can regulate the transcription of several genes including ß-catenin, Cullin l and lin-28 homolog A (LIN28A), etc. In addition, the abnormal expression of SETD7 can promote the proliferation, migration, invasion of tumor cells, predict the poor prognosis of tumor patients, and may be a potential target for tumor therapy. This paper reviews the structure of SETD7, its role in tumor genesis and development, and the current research progress of relevant targeted drugs to explore its regulatory mechanism in tumor genesis and development and the prospect of targeted therapy.

Machine learning-driven exploration of drug therapies for triple-negative breast cancer treatment.

Breast cancer is the second leading cause of cancer death in women among all cancer types. It is highly heterogeneous in nature, which means that the tumors have different morphologies and there is heterogeneity even among people who have the same type of tumor. Several staging and classifying systems have been developed due to the variability of different types of breast cancer. Due to high heterogeneity, personalized treatment has become a new strategy. Out of all breast cancer subtypes, triple-negative breast cancer (TNBC) comprises ∼10%-15%. TNBC refers to the subtype of breast cancer where cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptors (ERs, PRs, and HERs). Tumors in TNBC have a diverse set of genetic markers and prognostic indicators. We scanned the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases for potential drugs using human breast cancer cell lines and drug sensitivity data. Three different machine-learning approaches were used to evaluate the prediction of six effective drugs against the TNBC cell lines. The top biomarkers were then shortlisted on the basis of their involvement in breast cancer and further subjected to testing for radion resistance using data from the Cleveland database. It was observed that Panobinostat, PLX4720, Lapatinib, Nilotinib, Selumetinib, and Tanespimycin were six effective drugs against the TNBC cell lines. We could identify potential derivates that may be used against approved drugs. Only one biomarker (SETD7) was sensitive to all six drugs on the shortlist, while two others (SRARP and YIPF5) were sensitive to both radiation and drugs. Furthermore, we did not find any radioresistance markers for the TNBC. The proposed biomarkers and drug sensitivity analysis will provide potential candidates for future clinical investigation.

Lysine N-methyltransferase SETD7 promotes bladder cancer progression and immune escape via STAT3/PD-L1 cascade.

Background: The immunotherapy sensitivity of patients with bladder cancer (BCa) remains low. As the role of protein methylation in tumorigenesis and development becomes clearer, the role of lysine N-methyltransferase SET domain containing 7 (SETD7) in the progression and immune escape of BCa is worth studying. Methods: The correlation between lysine methyltransferase family and prognosis or immunotheray sensitivity of BCa patients were analyzed, and SETD7 was screened out because of the significant correlation between its expression and survival data or immunotherapy sensitivity. The expression of SETD7 in BCa tissues and cell lines were explored. The functions of SETD7 were investigated by proliferation and migration assays. The role of SETD7 in BCa immune escape was validated by analyzing the correlation between SETD7 expression and tumor microenvironment (TME)-related indicators. The results were further confirmed by conducting BCa cell-CD8+ T cell co-culture assays and tumorigenesis experiment in human immune reconstitution NOG mice (HuNOG mice). Bioinformatic prediction, CO-IP, qRT-PCR, and western blot were used to validate the SETD7/STAT3/PD-L1 cascade. Results: SETD7 was highly expressed in BCa, and it was positively associated with high histological grade and worse prognosis. SETD7 promoted the proliferation and migration of BCa cells. The results of bioinformatics, in vitro co-culture, and in vivo tumorigenesis assays showed that SETD7 could inhibit the chemotoxis and cytotoxicity of CD8+ T cells in BCa TME. Mechanistically, bioinformatics analysis, CO-IP assay, qRT-PCR, and western blot results indicated that SETD7 could increase the expression of PD-L1 via binding and promoting STAT3. Conclusions: Taken together, SETD7 indicated poor prognosis and promoted the progression and immune escape of BCa cells. It has great potential to act as a new indicator for BCa diagnosis and treatment, especially immunotherapy.

(R)-PFI-2 Analogues as Substrates and Inhibitors of Histone Lysine Methyltransferase SETD7.

(R)-PFI-2 is a histone substrate-competitive inhibitor of the human histone lysine monomethyltransferase SETD7. Aimed at developing potent inhibitors of SETD7 that can also act as small molecule substrates, we replaced the pyrrolidine ring of (R)-PFI-2 with several side chains bearing nucleophilic functional groups. We explored the inhibitory activity of 20 novel (R)-PFI-2 analogues, and found that the most potent analogue has a hydroxyethyl side chain (7). SETD7's ability to catalyse methylation of (R)-PFI-2-based small molecules was evaluated by mass spectrometric assays, and we observed efficient methylation of analogues bearing lysine mimicking nucleophilic amines. The optimal side chain was found to be an aminoethyl group (1), which was surprisingly also dimethylated by SETD7. The work demonstrates that small molecules can act as both substrates and inhibitors of biomedically important SETD7.

[Research Progress of Role and Mechanism of SETD7 in Tumor Occurrence 
and Progression].

The occurence and development of tumors is a complicated process, which not only depends on the mutation or deletion of genes, but also is affected by epigenetic regulation. Accumulating evidences have shown that epigenetic modifications play fundamental roles in transcriptional regulation, heterochromatin formation, X chromosome inactivation, DNA damage response and tumor development. SET domain containing lysine methyltransferase 7 (SETD7) was initially identified as an important lysine methyltransferase, which methylated histone and non-histone proteins. These modifications play fundamental roles. Once this modification disorders, it can directly lead to cell abnormalities and cause many diseases. Studies have shown that SETD7 is related to the occurence and development of various tumors, but the methylation sites of SETD7 and its regulatory mechanism have not been fully elucidated. This article summarizes the research progress of the role of SETD7 on histone and non-histone methylation modification in tumors and the molecular mechanism, in order to provide new therapeutic targets for tumor pathogenesis and diagnosis.
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DDB1 regulates the activation-induced apoptosis of T cells via downregulating the expression of histone methyltransferase SETD7.

The damaged DNA-binding protein 1 (DDB1) enhances the survival and maintenance of multipotent cells through promoting the Cullin 4 E3 ligase complex-dependent ubiquitination and subsequent degradation of downstream substrates. Naive T cells could be activated and differentiated into effector and memory T cells by exogenous stimulatory molecules, which are essential in immune response and inflammation. However, possible regulation and molecular mechanisms of DDB1 in T-cell activation-induced apoptosis were largely unknown. Here, in this study, we uncovered that DDB1 could downregulate the expression of histone methyltransferase SETD7 through decreasing its mRNA level and then regulated activation-induced apoptosis of T-cell line Jurkat cells. Furthermore, RNA-sequencing assay on activated Jurkat cells confirmed that the SETD7 attenuated the activation of Jurkat cells. Our study revealed the non-enzymatic functions of DDB1 on the activation-induced apoptosis of T cells.