Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis

Montenegro, María F.; Sánchez‐del‐Campo, Luis; González-Guerrero, R; Martínez‐Barba, Enrique; Piñero-Madrona, Antonio; Cabezas-Herrera, Juan; Rodrı́guez-López, José Neptuno

doi:10.1038/onc.2016.154

Cited by 37 publications

(55 citation statements)

References 55 publications

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“…SETD7 (also known as SET7/9) is a 41 kDa lysine-specific SET-domain methyltransferase, which is the only lysine methyltransferases (KMT)7 family member due to its unique enzymatic activity and protein domain architecture [ 23 ]. Recent investigations indicated that SETD7 is potentially a biomarker for hepatocellular cancer [ 24 ] and breast cancer [ 25 , 26 ], although the role of SETD7 in breast cancer is controversial [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Histone-lysine N-methyltransferase SETD7 is a potential serum biomarker for colorectal cancer patients

et al. 2018

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BackgroundThere is an urgent need for the identification of new, clinically useful biomarkers of CRC to enhance diagnostic and prognostic capabilities.MethodsWe performed proteomic profiling on serum samples from paired pre- and post-operative CRC patients, colorectal polyps patients and healthy controls using an approach combining magnetic bead-based weak cation exchange and matrix-assisted laser desorption ionization-time of flight mass spectrometry. We next performed liquid chromatography-electrospray ionization-tandem mass spectrometry to identify the proteins and selected potential biomarker based on bioinformatics analysis of the TCGA and GEO dataset. We examined SETD7 expression in serum and tissue samples by ELISA and immunohistochemistry respectively and explored the biological function of SETD7 in vitro.Findings85 differentially expressed peptides were identified. Five peptides showing the most significant changes in abundance across paired pre- and post-operation CRC patients, colorectal polyps patients and healthy controls were identified as peptide regions of FGA, MUC5AC and SETD7. Bioinformatics analysis suggested that the up-regulation of SETD7 in CRC is relatively specific. Validation studies showed that SETD7 expression increased from healthy controls to those with colorectal polyps and finally CRC patients, and decreased after surgery. The sensitivity and specificity of SETD7 were 92.17% and 81.08%, with a high diagnostic value (AUC = 0.9477). In addition, SETD7 expression was significantly correlated with tumor stage and microsatellite instability. Knockdown of SETD7 inhibited cancer cell proliferation, induced G1/S cell cycle arrest and increased apoptosis.InterpretationOur data indicate that SETD7 could serve as a potential diagnostic and prognostic biomarker for CRC.

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Section: Discussionmentioning

confidence: 99%

Histone-lysine N-methyltransferase SETD7 is a potential serum biomarker for colorectal cancer patients

et al. 2018

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“…As a member of histone lysine methyltransferase, SETD7 is also an important modifier of non‐histone proteins. While SETD7 probably drives the progression of gastric cancer, the modification of SETD7 would favour the tumour suppressor function of E2F1 in breast cancer . The important transcription factor KLF4, acted as a suppressor in metastasis and proliferation of cancer cells in colorectal cancer, while driven expression of KLF4 in tumour‐associated macrophages promoted immunosuppression to facilitate tumour growth in glioblastoma .…”

Section: Discussionmentioning

confidence: 99%

METTL3/YTHDF2 m⁶A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer

Xie

Ying

et al. 2020

J Cellular Molecular Medi

118

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| INTRODUC TI ONBladder cancer (BCa) is the most common malignant tumour of the urinary tract and the 10th most common type of carcinoma worldwide. Approximately 549 000 new cases and 200 000 deaths were estimated by GLOBOCAN in 2018. 1 In 2019, approximately 80 470 patients (including 61 700 men) were diagnosed with BCa and 17 670 patients (including 12 870 men) died from BCa in the United States; thus, BCa ranks the forth in incidence and eighth in mortality in men. 2 The increasing trend in these numbers constantly urges researchers to better understand the mechanisms underlying the pathogenesis of BCa to identify potential therapies against BCa. m 6 A, a modification first identified in mRNA-enriched RNA fractions in 1974, 3 refers to methylation of the N6 position of adenosine bases, which are widely distributed in the mammalian mRNA. 4,5 With the application of available methods for detecting m 6 A, insights into the regulatory mechanism have been revealed in recent years. m 6 A RNA modification is a dynamic and reversible posttranscriptional modification process maintained by a multicomponent Abstract N6-Methyladenosine (m 6 A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours.However, the specific role of m 6 A in bladder cancer (BCa) is still poorly understood.In this study, we demonstrated the tumour-promoting function and specific regulatory mechanism of m 6 A axis, consisting of the core 'writer' protein METTL3 and the major reader protein YTHDF2. Depletion of METTL3 impaired cancer proliferation and cancer metastasis in vitro and in vivo. Through transcriptome sequencing, m 6 A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m 6 A axis directly degraded the mRNAs of the tumour suppressors SETD7 and KLF4, contributing to the progression of BCa. In addition, overexpression of SETD7 and KLF4 revealed a phenotype consistent with that induced by depletion of the m 6 A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m 6 A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa. K E Y W O R D Sbladder cancer, carcinogenesis, METTL3/YTHDF2 m 6 A axis, mRNA degradation, RNA modification | 4093 XIE Et al.

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“…Evident expression of SET7/9 was detected in all the normal bone marrow samples and 48.6% of the clinical AML samples, but no expression or only weak expression was detected in the other 51.4% clinical AML samples (Figure 1 A), indicating down-regulation of SET7/9 expression in AML. Although SET7/9 was proposed to constitute a fine-tuning mechanism for the epigenetic modulation of different gene expression through methylation of promoter regions 31 , 32 , few studies have focused on the regulatory mechanisms controlling SET7/9 expression itself. Here we found that loss of SET7/9 expression in clinical AML samples and AML cell line KG-1a was related with the methylation of the CpG sites located in SET7/9 promoter (Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

Opposite Effects of SET7/9 on Apoptosis of Human Acute Myeloid Leukemia Cells and Lung Cancer Cells

Gu¹,

Wang²,

Wang³

et al. 2017

J. Cancer

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SET7/9 is a protein lysine methyltransferases (PLMTs or PKMTs) which methylates both histone H3K4 and non-histone proteins including transcriptional factors, tumor suppressors, and membrane-associated receptors. Methylation of these proteins alters protein activity and leads to changes in cellular behavior and a series of biological processes. This study aims to investigate the role of SET7/9 in human acute myeloid leukemia (AML) and non-small-cell lung cancer (NSCLC). We examined the expression of SET7/9 in AML cells and NSCLC cells and detected the methylation status of the SET7/9 promoter region. To evaluate the effect of SET7/9 expression changes on cell apoptosis, cell apoptosis rates were determined after SET7/9 overexpression or down-regulation. Our results showed that SET7/9 induces apoptosis of AML cells and inhibits apoptosis of NSCLC cells, suggesting differential effects of SET7/9 on cellular apoptosis and carcinogenesis depending on different cancer types and genetic contexts. Furthermore, we also demonstrated that SET7/9 suppresses cell apoptosis via modulation of E2F1 under circumstance of p53 deficiency in NSCLC cells.

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Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis

Cited by 37 publications

References 55 publications

Histone-lysine N-methyltransferase SETD7 is a potential serum biomarker for colorectal cancer patients

Histone-lysine N-methyltransferase SETD7 is a potential serum biomarker for colorectal cancer patients

METTL3/YTHDF2 m⁶A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer

Opposite Effects of SET7/9 on Apoptosis of Human Acute Myeloid Leukemia Cells and Lung Cancer Cells

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Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis

Cited by 37 publications

References 55 publications

Histone-lysine N-methyltransferase SETD7 is a potential serum biomarker for colorectal cancer patients

Histone-lysine N-methyltransferase SETD7 is a potential serum biomarker for colorectal cancer patients

METTL3/YTHDF2 m6A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer

Opposite Effects of SET7/9 on Apoptosis of Human Acute Myeloid Leukemia Cells and Lung Cancer Cells

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METTL3/YTHDF2 m⁶A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer