The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Xuegang Luo - One of the best experts on this subject based on the ideXlab platform.
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SMYD3 associated pathway is involved in the anti tumor effects of sulforaphane on gastric carcinoma cells
Food Science and Biotechnology, 2018Co-Authors: Qingqing Dong, Tongcun Zhang, Yong Liu, Lei Wang, Hao Zhou, Qiutong Wang, Yaxin Jiang, Meiling Liu, Xuegang LuoAbstract:Sulforaphane (SFN), a natural compound derived from cruciferous vegetables, has been proved to possess potent anti-cancer activity. SMYD3 is a histone methyltransferase which is closely related to the proliferation and migration of cancer cells. This study showed that SFN could dose-dependently induce cell cycle arrest, stimulate apoptosis, and inhibit proliferation and migration of gastric carcinoma cells. Accompanied with these anti-cancer effects, SMYD3 and its downstream genes, myosin regulatory light chain 9, and cysteine-rich angiogenic inducer 61, was downregulated by SFN. Furthermore, overexpression of SMYD3 via transfection could abolish the effects of SFN, suggesting that SMYD3 might be an important mediator of SFN. To the best of our knowledge, this is the first report describing the role of SMYD3 in the anti-cancer of SFN. These findings might throw light on the development of novel anti-cancer drugs and functional food using SFN-rich cruciferous vegetables.
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atm signaling pathway is implicated in the SMYD3 mediated proliferation and migration of gastric cancer cells
Journal of Gastric Cancer, 2017Co-Authors: Lei Wang, Tongcun Zhang, Yong Liu, Hao Zhou, Qingqing Dong, Qiutong Wang, Yupeng Liu, Zhi Miao, Xuegang LuoAbstract:Purpose We previously found that the histone methyltransferase suppressor of variegation, enhancer of zeste, trithorax and myeloid-nervy-deformed epidermal autoregulatory factor-1 domain-containing protein 3 (SMYD3) is a potential independent predictive factor or prognostic factor for overall survival in gastric cancer patients, but its roles seem to differ from those in other cancers. Therefore, in this study, the detailed functions of SMYD3 in cell proliferation and migration in gastric cancer were examined. Materials and Methods SMYD3 was overexpressed or suppressed by transfection with an expression plasmid or siRNA, and a wound healing migration assay and Transwell assay were performed to detect the migration and invasion ability of gastric cancer cells. Additionally, an MTT assay and clonogenic assay were performed to evaluate cell proliferation, and a cell cycle analysis was performed by propidium iodide staining. Furthermore, the expression of genes implicated in the ataxia telangiectasia mutated (ATM) pathway and proteins involved in cell cycle regulation were detected by polymerase chain reaction and western blot analyses. Results Compared with control cells, gastric cancer cells transfected with si-SMYD3 showed lower migration and invasion abilities (P<0.05), and the absence of SMYD3 halted cells in G2/M phase and activated the ATM pathway. Furthermore, the opposite patterns were observed when SMYD3 was elevated in normal gastric cells. Conclusions To the best of our knowledge, this study provides the first evidence that the absence of SMYD3 could inhibit the migration, invasion, and proliferation of gastric cancer cells and halt cells in G2/M phase via the ATM-CHK2/p53-Cdc25C pathway. These findings indicated that SMYD3 plays crucial roles in the proliferation, migration, and invasion of gastric cancer cells and may be a useful therapeutic target in human gastric carcinomas.
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effect of SMYD3 on the microrna expression profile of mcf 7 breast cancer cells
Oncology Letters, 2017Co-Authors: Dongju Chen, Xuegang Luo, Lei Liu, Lihua Yan, Xiaoying Chen, Lei Wang, Nan Wang, Hao Zhou, Tongcun ZhangAbstract:SET and MYND domain containing 3 (SMYD3) is a histone methyltransferase (HMT) and transcription factor, which serves important roles in carcinogenesis. Numerous downstream target genes of SMYD3 have been identified in previous studies. However, the downstream microRNA (miRNA) s regulated by SMYD3 are yet to be elucidated. In the present study, the results of miRNA microarray demonstrated that 30 miRNA expression profiles were upregulated, whilst 24 miRNAs were downregulated by >2.0-fold in the SMYD3-overexpressed MCF-7 breast cancer cells. The HMT activity was demonstrated to be essential for SMYD3-mediated transactivation of miR-200c-3p and the overexpression of miR-200c-3p inhibited the transactivation effects of SMYD3 on myocardin-related transcription factor-A-dependent migration-associated genes. To our best knowledge, the current study is the first to report on the transcriptional regulation of SMYD3 on miRNAs, and miR-200c may be a downstream negative regulator of the SMYD3-mediated pathway in the migration of breast cancer cells. These results may provide a novel theoretical basis to understand the mechanisms underlying the initiation, progression, diagnosis, prevention and therapy of breast cancer.
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SMYD3 overexpression was a risk factor in the biological behavior and prognosis of gastric carcinoma
Tumor Biology, 2015Co-Authors: Yong Liu, Xuegang Luo, Jingyu Deng, Yuan Pan, Li Zhang, Han LiangAbstract:SET and MYND domain-containing protein 3 (SMYD3), a histone methyltransferase, plays a key function in the progression of human cancer. However, the role of SMYD3 in gastric carcinoma carcinogenesis has yet to be elucidated. This study aimed to determine the relationships of SMYD3 expression with clinicopathological characteristics and prognosis in gastric carcinoma. The expression of SMYD3 was detected by real-time quantitative reverse transcription PCR and Western blot in gastric carcinoma (GC) cell lines, normal gastric mucosa cell line, GC tissues, and adjacent non-tumor tissues. SMYD3 expression in tissue sections of 180 gastric carcinoma samples were evaluated using immunohistochemistry. The staining results were compared with clinicopathological characteristics and to the outcome of patients. The expression levels of SMYD3 messenger RNA (mRNA) and protein in GC tissues were both higher than those in adjacent non-tumor tissues (p < 0.05). SMYD3 mRNA and protein expression levels were higher in GC cell lines MKN28, SGC7901, and MGC803 than normal gastric mucosa cell line GES-1. SMYD3 expression in gastric carcinoma was significantly correlated with primary tumor size (p < 0.001), lymph node metastasis (p < 0.001), and TNM stage (p = 0.011). Degree of differentiation [hazard ratio (HR) = 5.113; p = 0.006], serosal invasion (HR = 2.074; p = 0.024), lymph node metastasis (HR = 1.354; p < 0.001), and SMYD3 expression (HR = 0.564; p = 0.004) were identified as the independent factors of the overall survival (OS) in all enrolled GC patients. For patients with positive lymph node metastasis, degree of differentiation (HR = 5.974; p = 0.015), lymph node metastasis (HR = 1.257; p < 0.001), and SMYD3 expression (HR = 0.529; p = 0.004) were the independent prognostic factors of the OS. SMYD3 performed an important function in the aggressiveness of gastric carcinoma and may act as a promising target for prognostic prediction.
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overexpression of SMYD3 and matrix metalloproteinase 9 are associated with poor prognosis of patients with gastric cancer
Tumor Biology, 2015Co-Authors: Yong Liu, Xuegang Luo, Honggen Liu, Jingyu Deng, Yuan Pan, Han LiangAbstract:SET and MYND domain-containing protein 3 (SMYD3) plays a key role in the progression of human cancer. Matrix metalloproteinase (MMP)-9 is being related to tumor progression. It has been reported that SMYD3 and MMP-9 are overexpressed in human cancers. However, the exact roles of SMYD3 and MMP-9 in the metastasis and prognosis of gastric cancer (GC) remain unclear. The expressions of SMYD3 and MMP-9 were detected by semiquantitative reverse transcription polymerase chain reaction and Western blotting in gastric cancer and adjacent nontumor tissues. In addition, SMYD3 and MMP-9 expressions were analyzed by immunohistochemistry in formalin-fixed samples from 186 gastric cancer patients. The messenger RNA (mRNA) and protein expression levels of SMYD3 and MMP-9 in gastric cancer tissues were both significantly higher than those in adjacent nontumor tissues. In addition, the expression of SMYD3 was correlated with size of primary tumor and lymph node metastasis, while size of primary tumor and serosal invasion were identified as the independently relative factors of MMP-9 expression in GC tissues. SMYD3 expression and MMP-9 expression in GC tissues were significantly and positively correlated. Multivariate analysis results demonstrated that degree of differentiation, lymph node metastasis, TNM stage, SMYD3 expression, and MMP-9 expression were the independent prognostic indicators of gastric cancer. SMYD3 and MMP-9 may play important roles in tumor invasion, metastasis, and prognosis and could work as promising targets for prognostic prediction in gastric cancer.
Shuzhen Wang - One of the best experts on this subject based on the ideXlab platform.
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effects of SMYD3 over expression on cell cycle acceleration and cell proliferation in mda mb 231 human breast cancer cells
Medical Oncology, 2011Co-Authors: Tiannian Ren, Jingsong Wang, Shuzhen WangAbstract:SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis. It can specifically methylate histone H3 at lysine 4 and activate the transcription of a set of downstream genes, including several oncogenes (e.g., N-myc, CrkL, Wnt10b, RIZ and hTERT) and genes involved in the control of cell cycle (e.g., CyclinG1 and CDK2) and signal transduction (e.g., STAT1, MAP3K11 and PIK3CB). To determine the effects of SMYD3 over-expression on cell proliferation, we transfected SMYD3 into MDA-MB-231 cells and found that these cells showed several transformed phenotypes as demonstrated by colony growth in soft agar. Besides, we show here that down-regulation of SMYD3 could induce G1-phase cell cycle arrest, indicating the potent induction of apoptosis by SMYD3 knockdown. These results suggest the regulatory mechanisms of SMYD3 on the acceleration of cell cycle and facilitate the development of strategies that may inhibit the progression of cell cycle in breast cancer cells.
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novobiocin decreases SMYD3 expression and inhibits the migration of mda mb 231 human breast cancer cells
Iubmb Life, 2009Co-Authors: Xuegang Luo, Jianing Zou, Shuzhen Wang, Tongcun ZhangAbstract:SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis, and heat-shock protein HSP90A has been shown to increase the activity of SMYD3. We previously reported that overexpression of SMYD3 stimulated the migration of cells. In this study, we further found that novobiocin, a HSP90 inhibitor, could decrease the expression of SMYD3 and dose dependently inhibit the proliferation and migration of MDA-MB-231 human breast cancer cells. As a control, the short hairpin RNA (shRNA) targeting SMYD3 gene also showed similar effects with novobicin. This study is the first to show that novobiocin can inhibit the migration of breast cancer cells and such event may involve the downregulation of SMYD3. These findings might throw light on the development of novel therapeutic approaches to human cancers, and lend further understanding to the potential role of SMYD3 in human carcinogenesis. © 2009 IUBMB IUBMB Life, 62(3): 194–199, 2010
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novobiocin decreases SMYD3 expression and inhibits the migration of mda mb 231 human breast cancer cells
Iubmb Life, 2009Co-Authors: Xuegang Luo, Jianing Zou, Shuzhen Wang, Tongcun ZhangAbstract:SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis, and heat-shock protein HSP90A has been shown to increase the activity of SMYD3. We previously reported that overexpression of SMYD3 stimulated the migration of cells. In this study, we further found that novobiocin, a HSP90 inhibitor, could decrease the expression of SMYD3 and dose dependently inhibit the proliferation and migration of MDA-MB-231 human breast cancer cells. As a control, the short hairpin RNA (shRNA) targeting SMYD3 gene also showed similar effects with novobicin. This study is the first to show that novobiocin can inhibit the migration of breast cancer cells and such event may involve the downregulation of SMYD3. These findings might throw light on the development of novel therapeutic approaches to human cancers, and lend further understanding to the potential role of SMYD3 in human carcinogenesis.
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knockdown of SMYD3 by rna interference down regulates c met expression and inhibits cells migration and invasion induced by hgf
Cancer Letters, 2009Co-Authors: Jianing Zou, Xuegang Luo, Shuzhen Wang, Jiasen Yang, Jinghang XieAbstract:We previously reported that over-expression of SMYD3, a histone H3-K4 specific di- and tri-methyltransferase, plays a key role in cell viability, adhesion, migration and invasion. In this study, we investigated the mechanisms underlying these phenomena and found that knocking down SMYD3 expression in tumor cells significantly reduced the biological function of HGF and inhibited carcinoma cells migration and invasion. Due to the fact that the proto-oncogene c-Met encodes the high-affinity receptor for HGF, and the HGF-c-Met signaling plays a critical role in the tumor genesis, we further identified the partial correlation between SMYD3 and c-Met. The results showed that high expression of c-Met accompanied with over-expression of SMYD3. Silencing SMYD3 expression in tumor cells by specific shRNAs down-regulated c-Met gene transcription, while over-expressing SMYD3 induced c-Met transcription. Moreover, we demonstrated here that two SMYD3 binding sites within the c-Met core promoter region were significant in the transactivation of c-Met. The present findings provide significant insights into the epigenetic regulatory mechanisms of oncogene c-Met expression, and develop the strategies that may inhibit the progression of cancer migration and invasion.
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knockdown of SMYD3 by rna interference inhibits cervical carcinoma cell growth and invasion in vitro
Journal of Biochemistry and Molecular Biology, 2008Co-Authors: Shuzhen Wang, Xuegang Luo, Jing Shen, Jianing ZouAbstract:Elevated expression of SMYD3 is a frequent genetic abnormality in several malignancies. Few studies knocking down SMYD3 expression in cervical carcinoma cells have been performed to date. In this paper, we established an inducible short hairpin RNA expression system to examine its role in maintaining the malignant phenotype of HeLa cells. After being induced by doxycycline, SMYD3 mRNA and protein expression were both reduced, and significant reductions in cell proliferation, colony formation and migration/invasion activity were observed in the SMYD3-silenced HeLa cells. The percentage of cells in sub-G1 was elevated and DNA ladder formation could be detected, indicating potent induction of apoptosis by SMYD3 knockdown. These findings imply that SMYD3 plays crucial roles in HeLa cell proliferation and migration/invasion, and that it may be a useful therapeutic target in human cervical carcinomas.
Tongcun Zhang - One of the best experts on this subject based on the ideXlab platform.
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SMYD3 associated pathway is involved in the anti tumor effects of sulforaphane on gastric carcinoma cells
Food Science and Biotechnology, 2018Co-Authors: Qingqing Dong, Tongcun Zhang, Yong Liu, Lei Wang, Hao Zhou, Qiutong Wang, Yaxin Jiang, Meiling Liu, Xuegang LuoAbstract:Sulforaphane (SFN), a natural compound derived from cruciferous vegetables, has been proved to possess potent anti-cancer activity. SMYD3 is a histone methyltransferase which is closely related to the proliferation and migration of cancer cells. This study showed that SFN could dose-dependently induce cell cycle arrest, stimulate apoptosis, and inhibit proliferation and migration of gastric carcinoma cells. Accompanied with these anti-cancer effects, SMYD3 and its downstream genes, myosin regulatory light chain 9, and cysteine-rich angiogenic inducer 61, was downregulated by SFN. Furthermore, overexpression of SMYD3 via transfection could abolish the effects of SFN, suggesting that SMYD3 might be an important mediator of SFN. To the best of our knowledge, this is the first report describing the role of SMYD3 in the anti-cancer of SFN. These findings might throw light on the development of novel anti-cancer drugs and functional food using SFN-rich cruciferous vegetables.
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atm signaling pathway is implicated in the SMYD3 mediated proliferation and migration of gastric cancer cells
Journal of Gastric Cancer, 2017Co-Authors: Lei Wang, Tongcun Zhang, Yong Liu, Hao Zhou, Qingqing Dong, Qiutong Wang, Yupeng Liu, Zhi Miao, Xuegang LuoAbstract:Purpose We previously found that the histone methyltransferase suppressor of variegation, enhancer of zeste, trithorax and myeloid-nervy-deformed epidermal autoregulatory factor-1 domain-containing protein 3 (SMYD3) is a potential independent predictive factor or prognostic factor for overall survival in gastric cancer patients, but its roles seem to differ from those in other cancers. Therefore, in this study, the detailed functions of SMYD3 in cell proliferation and migration in gastric cancer were examined. Materials and Methods SMYD3 was overexpressed or suppressed by transfection with an expression plasmid or siRNA, and a wound healing migration assay and Transwell assay were performed to detect the migration and invasion ability of gastric cancer cells. Additionally, an MTT assay and clonogenic assay were performed to evaluate cell proliferation, and a cell cycle analysis was performed by propidium iodide staining. Furthermore, the expression of genes implicated in the ataxia telangiectasia mutated (ATM) pathway and proteins involved in cell cycle regulation were detected by polymerase chain reaction and western blot analyses. Results Compared with control cells, gastric cancer cells transfected with si-SMYD3 showed lower migration and invasion abilities (P<0.05), and the absence of SMYD3 halted cells in G2/M phase and activated the ATM pathway. Furthermore, the opposite patterns were observed when SMYD3 was elevated in normal gastric cells. Conclusions To the best of our knowledge, this study provides the first evidence that the absence of SMYD3 could inhibit the migration, invasion, and proliferation of gastric cancer cells and halt cells in G2/M phase via the ATM-CHK2/p53-Cdc25C pathway. These findings indicated that SMYD3 plays crucial roles in the proliferation, migration, and invasion of gastric cancer cells and may be a useful therapeutic target in human gastric carcinomas.
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effect of SMYD3 on the microrna expression profile of mcf 7 breast cancer cells
Oncology Letters, 2017Co-Authors: Dongju Chen, Xuegang Luo, Lei Liu, Lihua Yan, Xiaoying Chen, Lei Wang, Nan Wang, Hao Zhou, Tongcun ZhangAbstract:SET and MYND domain containing 3 (SMYD3) is a histone methyltransferase (HMT) and transcription factor, which serves important roles in carcinogenesis. Numerous downstream target genes of SMYD3 have been identified in previous studies. However, the downstream microRNA (miRNA) s regulated by SMYD3 are yet to be elucidated. In the present study, the results of miRNA microarray demonstrated that 30 miRNA expression profiles were upregulated, whilst 24 miRNAs were downregulated by >2.0-fold in the SMYD3-overexpressed MCF-7 breast cancer cells. The HMT activity was demonstrated to be essential for SMYD3-mediated transactivation of miR-200c-3p and the overexpression of miR-200c-3p inhibited the transactivation effects of SMYD3 on myocardin-related transcription factor-A-dependent migration-associated genes. To our best knowledge, the current study is the first to report on the transcriptional regulation of SMYD3 on miRNAs, and miR-200c may be a downstream negative regulator of the SMYD3-mediated pathway in the migration of breast cancer cells. These results may provide a novel theoretical basis to understand the mechanisms underlying the initiation, progression, diagnosis, prevention and therapy of breast cancer.
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novobiocin decreases SMYD3 expression and inhibits the migration of mda mb 231 human breast cancer cells
Iubmb Life, 2009Co-Authors: Xuegang Luo, Jianing Zou, Shuzhen Wang, Tongcun ZhangAbstract:SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis, and heat-shock protein HSP90A has been shown to increase the activity of SMYD3. We previously reported that overexpression of SMYD3 stimulated the migration of cells. In this study, we further found that novobiocin, a HSP90 inhibitor, could decrease the expression of SMYD3 and dose dependently inhibit the proliferation and migration of MDA-MB-231 human breast cancer cells. As a control, the short hairpin RNA (shRNA) targeting SMYD3 gene also showed similar effects with novobicin. This study is the first to show that novobiocin can inhibit the migration of breast cancer cells and such event may involve the downregulation of SMYD3. These findings might throw light on the development of novel therapeutic approaches to human cancers, and lend further understanding to the potential role of SMYD3 in human carcinogenesis. © 2009 IUBMB IUBMB Life, 62(3): 194–199, 2010
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novobiocin decreases SMYD3 expression and inhibits the migration of mda mb 231 human breast cancer cells
Iubmb Life, 2009Co-Authors: Xuegang Luo, Jianing Zou, Shuzhen Wang, Tongcun ZhangAbstract:SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis, and heat-shock protein HSP90A has been shown to increase the activity of SMYD3. We previously reported that overexpression of SMYD3 stimulated the migration of cells. In this study, we further found that novobiocin, a HSP90 inhibitor, could decrease the expression of SMYD3 and dose dependently inhibit the proliferation and migration of MDA-MB-231 human breast cancer cells. As a control, the short hairpin RNA (shRNA) targeting SMYD3 gene also showed similar effects with novobicin. This study is the first to show that novobiocin can inhibit the migration of breast cancer cells and such event may involve the downregulation of SMYD3. These findings might throw light on the development of novel therapeutic approaches to human cancers, and lend further understanding to the potential role of SMYD3 in human carcinogenesis.
Nicolas Reynoird - One of the best experts on this subject based on the ideXlab platform.
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novel insights into the oncogenic function of the SMYD3 lysine methyltransferase
Translational cancer research, 2016Co-Authors: Pawel K Mazur, Or Gozani, Julien Sage, Nicolas ReynoirdAbstract:SMYD3 is a member of the SMYD family of lysine methyltransferases (KMTs). In humans, there are five SMYD members (SMYD1–5) that are characterized by the presence of a split catalytic SET domain interrupted by a MYND zinc finger domain. The MYND domain is thought to potentially mediate DNA or protein binding but a clear function is yet to be established. SMYD homologs have been described in a wide range of organisms, such as zebrafish, drosophila and budding yeast (1,2). While methylation activity has been clearly established for SMYD2 and SMYD3 (3-6), the activities of SMYD1, 4 and 5 are not well understood.
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SMYD3 links lysine methylation of map3k2 to ras driven lung cancer
European Respiratory Journal, 2015Co-Authors: Pawel K Mazur, Nicolas Reynoird, Julien Sage, Or GozaniAbstract:Deregulation of lysine methylation signalling has emerged as a common aetiological factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumours. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP kinase signalling and promotes the formation of Ras-driven carcinomas. Using mouse models for lung adenocarcinoma, we found that abrogating SMYD3 catalytic activity inhibits tumour development in response to oncogenic Ras. We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signalling module and SMYD3 depletion synergizes with a MEK inhibitor to block Ras driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signalling in lung cancer.
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SMYD3 links lysine methylation of map3k2 to ras driven cancer
Nature, 2014Co-Authors: Pawel K Mazur, Nicolas Reynoird, Purvesh Khatri, Pascal W T C Jansen, Alex W Wilkinson, Olena Barbash, Glenn S Van Aller, Michael J Huddleston, Dashyant DhanakAbstract:SMYD3 is a methyltransferase overexpressed in several human tumours; here methylation of the MAP3K2 kinase by SMYD3 is shown to be critical for Ras-induced tumour development in mouse models and human tumour cells, showing an unexpected role for methylation in a kinase signalling pathway and revealing a candidate therapeutic target. SMYD3 is a largely cytoplasmic lysine methyltransferase that is overexpressed in several human tumours. This paper reports that SMYD3 is required for Ras-induced tumour development in mouse models. The enzyme methylates MAP3K2, which inhibits binding of a phosphatase and potentiates the Ras/Raf signalling pathway. These results reveal an unexpected role for lysine methylation in a kinase signalling pathway and establish SMYD3 as a potential therapeutic target. Deregulation of lysine methylation signalling has emerged as a common aetiological factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics1. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumours2,3,4. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP kinase signalling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, we found that abrogating SMYD3 catalytic activity inhibits tumour development in response to oncogenic Ras. We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signalling module and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signalling.
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SMYD3 links lysine methylation of map3k2 to ras driven cancer
Nature, 2014Co-Authors: Pawel K Mazu, Nicolas Reynoird, Purvesh Khatri, Pascal W T C Janse, Ale W Wilkinso, Shichong Liu, Olena Arbash, Gle S Van Alle, Michael J Huddlesto, Dashyant DhanakAbstract:Deregulation of lysine methylation signalling has emerged as a common aetiological factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumours. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP kinase signalling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, we found that abrogating SMYD3 catalytic activity inhibits tumour development in response to oncogenic Ras. We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signalling module and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signalling.
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abstract 3145 SMYD3 catalyzes a novel methylation mark and regulates cancer cell proliferation
Cancer Research, 2012Co-Authors: Glenn S Vanaller, Nicolas Reynoird, Olena Barbash, Michael J Huddleston, Or Gozani, Roland S Annan, Ben A Garcia, Peter J Tummino, Ryan G KrugerAbstract:SET and MYND domain-containing protein 3 (SMYD3) is a lysine methyltransferase over-expressed in liver, breast and rectal carcinomas. We have shown that knockdown of SMYD3 has an anti-proliferative effect in cancer cell lines and that this effect can be rescued with wild type but not catalytically inactive SMYD3, directly linking SMYD3 catalytic activity to proliferation. Published reports indicate SMYD3 methylates lysine 4 of histone H3, lysine 20 of histone H4 and VEGFR1. However, activity testing of a peptide library and intact recombinant nucleosomes indicate that a unique methylation mark is catalyzed by SMYD3. LC-MS/MS analysis of in vitro reaction products have identified the location of this novel site of methylation. The existence of this novel mark and its dependence on SMYD3 activity was confirmed in cancer cells and mouse embryonic fibroblasts. We speculate that overexpression of SMYD3 causes aberrant methylation and plays an important role in the deregulation of gene expression leading to uncontrolled cellular proliferation in cancer making SMYD3 a promising target for anti-cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3145. doi:1538-7445.AM2012-3145
Vassiliki Saloura - One of the best experts on this subject based on the ideXlab platform.
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abstract 2117 immunomodulatory functions of SMYD3 in hpv negative head and neck squamous cell carcinoma
Cancer Research, 2021Co-Authors: Nupur Nigam, Benjamin J Bernard, Kyunghee Burkitt, Yvette Robbins, Sohyoung Kim, Richard L Bennett, Jonathan D Licht, Vassiliki SalouraAbstract:Background: Head and neck squamous cell carcinoma (HNSCC) causes approximately 10,000 deaths annually in the United States, with human-papilloma-virus (HPV)-negative patients having a particularly poor prognosis. Pembrolizumab, a programmed-death-1 (PD-1) antibody, was recently approved as a first-line therapy for patients with relapsed disease, however response rates are as low as 19%, underscoring the need for an improved understanding of immunotherapy resistance mechanisms. We have previously shown that HPV-negative HNSCC tumors with higher mRNA levels of SET and MYND Domain Containing 3 (SMYD3), a chromatin modifier known to trimethylated H3K4 (H3K4me3), have significantly lower mRNA levels of CD8 and CD8+ T-cell attracting chemokines, and that SMYD3 depletion in HNSCC cells in vitro leads to upregulation of CD8+ T-cell attracting chemokines. The goal of this work was to elucidate epigenetic mechanisms of immune evasion mediated by SMYD3 in HPV-negative HNSCC. Methods: siRNA- mediated SMYD3 knockdown was performed for 3 days to investigate immuno-modulatory epigenetic mechanisms mediated by SMYD3. RT-qPCR for immune-related genes, Western blotting for histone marks, ChIP-sequencing for H3K4me3, ChIP-qPCRs to determine genomic interactions of SMYD3 and ATAC-sequencing were performed. SMYD3 and CD8 immunohistochemical staining (IHC) of normal squamous, dysplastic epithelium and HPV-negative HNSCC tumors was also performed. Results: siRNA mediated knockdown of SMYD3 resulted in enrichment of inflammatory pathways and upregulation of type 1 interferon response and antigen presentation machinery genes in HNSCC cell lines. Immunoblotting for histone marks showed no reduction in H3K4me3 following SMYD3 depletion for 3 days. ChIP-sequencing for H3K4me3 showed differential distribution pattern with an increase of H3K4me3 peaks on immune-related genes, and a decrease of H3K4me3 on UHRF1, a reader of the repressive histone mark H3K9me3. RNA-seq, RT-PCR and ChIP-qPCR showed that SMYD3 may regulate the transcription of UHRF1 by binding to its promoter. SMYD3 depletion also led to decreased protein levels of UHRF1. ChIP for UHRF1 and H3K9me3 showed that UHRF1 binds directly on the promoters of CXCL9 and CXCL10 which are enriched for H3K9me3. IHC on Normal Squamous Epithelium and Squamous Cell Carcinoma tissues of increasing cancer stages showed increase in SMYD3 levels with the higher stage of cancer, and an inverse correlation with CD8+ T cell infiltration within the tumors. Conclusion: This is the first study reporting that the chromatin modifier SMYD3 may attenuate type I IFN responses in HPV-negative HNSCC by regulating the expression of a major epigenetic regulator, UHRF1, which may silence the expression of immune-related genes through H3K9me3. Citation Format: Nupur Nigam, Benjamin Jonah Bernard, Kyunghee Burkitt, Sohyoung Kim, Yvette Robbins, Richard L. Bennett, Jonathan D. Licht, Vassiliki Saloura. Immunomodulatory functions of SMYD3 in HPV-negative head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2117.
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SMYD3 a regulator of epigenetic and signaling pathways in cancer
Clinical Epigenetics, 2021Co-Authors: Benjamin J Bernard, Nupur Nigam, Kyunghee Burkitt, Vassiliki SalouraAbstract:Chromatin modifiers and their implications in oncogenesis have been an exciting area of cancer research. These are enzymes that modify chromatin via post-translational modifications such as methylation, acetylation, sumoylation, phosphorylation, in addition to others. Depending on the modification, chromatin modifiers can either promote or repress transcription. SET and MYN-domain containing 3 (SMYD3) is a chromatin modifier that has been implicated in the development and progression of various cancer types. It was first reported to tri-methylate Histone 3 Lysine 4 (H3K4), a methylation mark known to promote transcription. However, since this discovery, other histone (H4K5 and H4K20, for example) and non-histone (VEGFR, HER2, MAP3K2, ER, and others) substrates of SMYD3 have been described, primarily in the context of cancer. This review aims to provide a background on basic characteristics of SMYD3, such as its protein structure and tissue expression profiles, discuss reported histone and non-histone substrates of SMYD3, and underscore prognostic and functional implications of SMYD3 in cancer. Finally, we briefly discuss ongoing efforts to develop inhibitors of SMYD3 for future therapeutic use. It is our hope that this review will help synthesize existing research on SMYD3 in an effort to propel future discovery.
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abstract 3651 deciphering immunomodulatory roles of the SMYD3 methyltransferase in hpv negative head and neck squamous cell carcinoma
Cancer Research, 2020Co-Authors: Benjamin J Bernard, Nupur Nigam, Kyunghee Burkitt, Yvette Robbins, Clint T Allen, Lyuba Varticovski, Gordon L Hager, Carter Van Waes, Vassiliki SalouraAbstract:Human Papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is a cancer with a 50% recurrence rate and poor overall survival. While immunotherapy with programmed-death-1 (PD-1) checkpoint inhibitors was recently approved in the first-line recurrent/metastatic setting, response rates are as low as 20%. A main reason for this is that a majority of these tumors have a low CD8+ T-cell intratumoral infiltrate, rendering primary resistance to T-cell based immunotherapy. We recently found that SET and MYND Domain containing 3 (SMYD3), a chromatin modifier that trimethylates histone 3 lysine 4 (H3K4me3), is overexpressed in HPV-negative HNSCC compared to normal epithelium, and that higher expression of SMYD3 is associated with lower mRNA levels of CD8A and CXCL9, 10 and 11 chemokines, which are key mediators of CD8+ T-cell trafficking, in HPV-negative HNSCC tumors (TCGA). Furthermore, SMYD3 depletion induced upregulation of CXCL9, 10, and 11 in human HNSCC cells in vitro. The purpose of this study is to evaluate whether targeting SMYD3 increases intratumoral CD8+ T-cell infiltration and enhances responses to PD-1 checkpoint inhibition, and to decipher relevant mechanisms. To investigate this hypothesis, a syngeneic, heterotopic mouse model (C57BL/6) using a doxycycline-inducible SMYD3 knockdown HPV-negative mouse oral carcinoma cell line (MOC1) was generated. Experiments to assess whether SMYD3 knockdown alone and in combination with PD-1 inhibition induce tumor growth restraint are planned. RT-PCR to evaluate the effects of SMYD3 depletion on the expression of immune-related (type I IFN response and antigen presentation machinery) genes in the doxycycline-inducible MOC1 cell line, as well as in parental MOC1 cells using siRNA interference is being conducted. Western blotting to assess the effect of SMYD3 depletion on global histone methylation marks is also being conducted. Furthermore, to assess whether SMYD3 has a cell autonomous effect on the growth of MOC1 cells, cell viability assays (MTT) and cell cycle analysis are being pursued. Preliminary results have shown that SMYD3 depletion in parental MOC1 cells induced significant upregulation of mouse cxcl9 and 10. SMYD3 depletion also led to significant cell death in parental MOC1 cells. Experiments to assess the effect of SMYD3 depletion on CD8+ T-cell infiltration and tumor growth restraint in vivo are ongoing. This is the first study to investigate the role of SMYD3 as a regulator of antitumor immune response, and may lay the rationale to translate SMYD3 inhibitors in patients with HPV-negative HNSCC with the goal to render them susceptible to T-cell based immunotherapeutic approaches. Citation Format: Benjamin Bernard, Kyunghee Burkitt, Yvette Robbins, Nupur Nigam, Clint Allen, Lyuba Varticovski, Gordon Hager, Carter Van Waes, Vassiliki Saloura. Deciphering immunomodulatory roles of the SMYD3 methyltransferase in HPV-negative head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3651.