The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells

Nakai, Keiichi; Xia, Weiya; Liao, Hsin Wei; Saito, Mitsue; Hung, Mien‐Chie; Yamaguchi, Hirohito

doi:10.1007/s12282-017-0790-z

Cited by 81 publications

(106 citation statements)

References 25 publications

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“…EGFR is a commonly mutant gene in many malignant tumors. EGFR is often overexpressed in breast cancer, especially in triple-negative breast cancer 37, while hypermethylation of EGFR can contribute to cetuximab resistance 38. FGF2 involves in cell proliferation and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Significant prognostic values of differentially expressed-aberrantly methylated hub genes in breast cancer

Zhou

Chen³

et al. 2019

J. Cancer

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Introduction: Abnormal status of gene expression plays an important role in tumorigenesis, progression and metastasis of breast cancer. Mechanisms of gene silence or activation were varied. Methylation of genes may contribute to alteration of gene expression. This study aimed to identify differentially expressed hub genes which may be regulated by DNA methylation and evaluate their prognostic value in breast cancer by bioinformatic analysis. Methods: GEO2R was used to obtain expression microarray data from GSE54002, GSE65194 and methylation microarray data from GSE20713, GSE32393. Differentially expressed-aberrantly methylated genes were identified by FunRich. Biological function and pathway enrichment analysis were conducted by DAVID. PPI network was constructed by STRING and hub genes was sorted by Cytoscape. Expression and DNA methylation of hub genes was validated by UALCAN and MethHC. Clinical outcome analysis of hub genes was performed by Kaplan Meier-plotter database for breast cancer. IHC was performed to analyze protein levels of EXO1 and Kaplan-Meier was used for survival analysis. Results: 677 upregulated-hypomethylated and 361 downregulated-hypermethylated genes were obtained from GSE54002, GSE65194, GSE20713 and GSE32393 by GEO2R and FunRich. The most significant biological process, cellular component, molecular function enriched and pathway for upregulated-hypomethylated genes were viral process, cytoplasm, protein binding and cell cycle respectively. For downregulated-hypermethylated genes, the result was peptidyl-tyrosine phosphorylation, plasma membrane, transmembrane receptor protein tyrosine kinase activity and Rap1 signaling pathway (All p< 0.05). 12 hub genes (TOP2A, MAD2L1, FEN1, EPRS, EXO1, MCM4, PTTG1, RRM2, PSMD14, CDKN3, H2AFZ, CCNE2) were sorted from 677 upregulated-hypomethylated genes. 4 hub genes (EGFR, FGF2, BCL2, PIK3R1) were sorted from 361 downregulated-hypermethylated genes. Differential expression of 16 hub genes was validated in UALCAN database (p<0.05). 7 in 12 upregulated-hypomethylated and 2 in 4 downregulated-hypermethylated hub genes were confirmed to be significantly hypomethylated or hypermethylated in breast cancer using MethHC database (p<0.05). Finally, 12 upregulated hub genes (TOP2A, MAD2L1, FEN1, EPRS, EXO1, MCM4, PTTG1, RRM2, PSMD14, CDKN3, H2AFZ, CCNE2) and 3 downregulated genes (FGF2, BCL2, PIK3R1) contributed to significant unfavorable clinical outcome in breast cancer (p<0.05). High expression level of EXO1 protein was significantly associated with poor OS in breast cancer patients (p=0.03).

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Section: Discussionmentioning

confidence: 99%

Significant prognostic values of differentially expressed-aberrantly methylated hub genes in breast cancer

Zhou

Chen³

et al. 2019

J. Cancer

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“…anisms remain to be further characterized, it has been proposed that PRMT1 methylates the EGF receptor to promote colorectal cancer growth (28). Also, PRMT1 was shown to methylate a splicing isoform of the AML1-ETO fusion protein that acts as a transcription factor, thus facilitating the expression of target genes while also epigenetically controlling their methylation on histone 4 (31).…”

Section: Smad7 Methylation By Prmt1 Controls Tgf-␤ Signaling and Emtmentioning

confidence: 99%

Arginine methylation of SMAD7 by PRMT1 in TGF-β–induced epithelial–mesenchymal transition and epithelial stem-cell generation

Katsuno

Qin

Oses-Prieto

et al. 2018

Journal of Biological Chemistry

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The epithelial-to-mesenchymal transdifferentiation (EMT) is crucial for tissue differentiation in development and drives essential steps in cancer and fibrosis. EMT is accompanied by reprogramming of gene expression and has been associated with the epithelial stem-cell state in normal and carcinoma cells. The cytokine transforming growth factor β (TGF-β) drives this program in cooperation with other signaling pathways and through TGF-β-activated SMAD3 as the major effector. TGF-β-induced SMAD3 activation is inhibited by SMAD7 and to a lesser extent by SMAD6, and SMAD6 and SMAD7 both inhibit SMAD1 and SMAD5 activation in response to the TGF-β-related bone morphogenetic proteins (BMPs). We previously reported that, in response to BMP, protein arginine methyltransferase 1 (PRMT1) methylates SMAD6 at the BMP receptor complex, thereby promoting its dissociation from the receptors and enabling BMP-induced SMAD1 and SMAD5 activation. We now provide evidence that PRMT1 also facilitates TGF-β signaling by methylating SMAD7, which complements SMAD6 methylation. We found that PRMT1 is required for TGF-β-induced SMAD3 activation, through a mechanism similar to that of BMP-induced SMAD6 methylation, and thus promotes the TGF-β-induced EMT and epithelial stem-cell generation. This critical mechanism positions PRMT1 as an essential mediator of TGF-β signaling that controls the EMT and epithelial cell stemness through SMAD7 methylation.

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“…PRMT1 regulates tumour growth and metastasis in human melanoma via targeting ALCAM [10]. In triple-negative breast cancer, PRMT1 is critical for epidermal growth factor receptor (EGFR) activity, and inhibiting PRMT1 may be an effective therapeutic strategy for overcoming intrinsic cetuximab resistance in triplenegative breast cancer cells [11]. Similarly, in oesophageal squamous cell carcinoma, PRMT1 activates Hedgehog signalling and upregulates the expression of target genes downstream of Hedgehog signalling to promote the growth and migration of esophageal squamous cell carcinoma (ESCC) cells [12].…”

Section: Introductionmentioning

confidence: 99%

PRMT1 Promoted HCC Growth and Metastasis In Vitro and In Vivo via Activating the STAT3 Signalling Pathway

Zhang

Jiang

Zhong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Although it has been widely accepted that protein arginine methyltransferase 1 (PRMT1) is a cancer-promoting gene in various cancers, the mechanism of PRMT1 in hepatocellular carcinoma (HCC) requires more exploration. This study aimed to investigate the role of PRMT1 in HCC growth and metastasis. Methods: We compared PRMT1 expression and clinicopathological characteristics using paired HCC and adjacent noncancerous liver tissues from 210 patients and immunohistochemistry analyses. Cell proliferation, colony formation and migration were determined in HCC cell lines with PRMT1 overexpression or downregulation through MTT, crystal violet and Boyden chamber assays. Tumour growth was monitored in a xenograft model, and intrahepatic metastasis models were established. Results: PRMT1 expression was greatly increased in clinical HCC samples and strongly associated with poor prognosis and recurrence; PRMT1 expression was also positively correlated with microvascular invasion (P = 0.024), tumour differentiation (P = 0.014), tumour size (P = 0.002), and portal vein tumour thrombus (PVTT) (P = 0.028). Cell proliferation, colony formation and migration in vitro were enhanced by PRMT1 upregulation and decreased by PRMT1 downregulation in HCC cell lines. Moreover, low PRMT1 expression resulted in slow tumour growth and decreased tumour weight in vivo, as well as tumour metastasis. These phenotypes were associated with STAT3 signalling pathway activation. Cryptotanshinone, a STAT3 inhibitor, inhibited STAT3 phosphorylation and reversed the HCC phenotype of PRMT1 expression. Conclusions: We revealed a significant role for PRMT1 in HCC progression and metastasis in vitro and in vivo via STAT3 signalling pathway activation. PRMT1 may be a potential novel prognostic biomarker and new therapeutic target for HCC.

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The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells

Abstract: The results indicate that PRMT1 is critical for EGFR activity in 468 cells. Our data also suggest that inhibition of PRMT1 sensitizes TNBC cells to cetuximab. Thus, inhibition of PRMT1 may be an effective therapeutic strategy to overcome intrinsic resistance to cetuximab in TNBC.

Cited by 81 publications

References 25 publications

Significant prognostic values of differentially expressed-aberrantly methylated hub genes in breast cancer

Significant prognostic values of differentially expressed-aberrantly methylated hub genes in breast cancer

Arginine methylation of SMAD7 by PRMT1 in TGF-β–induced epithelial–mesenchymal transition and epithelial stem-cell generation

PRMT1 Promoted HCC Growth and Metastasis In Vitro and In Vivo via Activating the STAT3 Signalling Pathway

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