PRMT5 promotes epithelial‐mesenchymal transition via EGFR‐β‐catenin axis in pancreatic cancer cells

Ge, Lu; Wang, Huizhi; Xu, Xiao; Zhou, Zhengrong; He, Jianyu; Peng, Wan-Xin; Du, F.; Zhang, Youli; Gong, Aihua; Xu, Min

doi:10.1111/jcmm.14894

Cited by 34 publications

(37 citation statements)

References 25 publications

(69 reference statements)

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“…Accumulating evidence shows that nuclear accumulation of β-catenin play crucial role in regulating EMT [ 33 , 34 ]. Recently, Dong Xiao et al found that SPHK2, a direct target of miR-708, triggered a cascade of signals leading to the activation of Akt pathway and the phosphorylation of GSK-3β and finally to the nuclear translocation of β-catenin to regulate EMT in glioma cells [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induced ferritin light chain (FTL) promoted epithelia mesenchymal transition and chemoresistance of glioma

Liu

Gao

Zhan

et al. 2020

J Exp Clin Cancer Res

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Background Hypoxia, a fundamental characteristic of glioma, is considered to promote tumor malignancy by inducing process of epithelial mesenchymal transition (EMT). Ferritin Light Chain (FTL) is one of the iron metabolism regulators and is overexpressed in glioma. However, relationship between hypoxia and FTL expression and its role in regulating EMT remains unclear. Methods Immunohistochemistry (IHC), western blot and public datasets were used to evaluate FTL level in glioma. Wound healing, transwell assays, CCK8, annexin V staining assay were used to measure migration, invasion, proliferation and apoptosis of glioma cells in vitro. Interaction between HIF1A and FTL was assessed by luciferase reporter and Chromatin immunoprecipitation (ChIP) assays. Subcutaneous xenograft model was established to investigate in vivo growth. Results FTL expression was enriched in high grade glioma (HGG) and its expression significantly associated with IDH1/2 wildtype and unfavorable prognosis of glioma patients. FTL expression positively correlated with HIF1A in glioma tissues and obviously increased in U87 and U251 cells under hypoxia in a time-dependent manner. Mechanistically, HIF-1α regulates FTL expression by directly binding to HRE-3 in FTL promoter region. Furthermore, we found that knockdown FTL dramatically repressed EMT and reduced migration and invasion of glioma by regulating AKT/GSK3β/ β-catenin signaling both in vitro and in vivo. Moreover, our study found downregulation FTL decreased the survival rate and increased the apoptosis of glioma cells treated with temozolomide (TMZ). FTL expression segregated glioma patients who were treated with TMZ or with high MGMT promoter methylation into survival groups in TCGA dataset. Patients with methylated MGMT who had high FTL expression presented similar prognosis with patients with unmethylated MGMT. Conclusion Our study strongly suggested that hypoxia-inducible FTL was a regulator of EMT and acted not only as a prognostic marker but also a novel biomarker of response to TMZ in glioma.

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Section: Discussionmentioning

confidence: 99%

Hypoxia induced ferritin light chain (FTL) promoted epithelia mesenchymal transition and chemoresistance of glioma

Liu

Gao

Zhan

et al. 2020

J Exp Clin Cancer Res

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“…Activation of the epithelial-mesenchymal transition (EMT) program is considered a key mechanism by which cancer epithelial cells acquire a malignant phenotype [36] , [37] . PRMT5 promotes EMT probably via EGFR/AKT/β-catenin pathway in pancreatic cancer [38] . PRMT5/MEP50 are necessary to maintain EMT markers and enhance epigenetic mechanisms of TGF-β response [7] .…”

Section: Discussionmentioning

confidence: 99%

Targeting methyltransferase PRMT5 retards the carcinogenesis and metastasis of HNSCC via epigenetically inhibiting Twist1 transcription

Zeng

et al. 2020

Neoplasia

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Protein arginine methyltransferase 5 (PRMT5) is an important type II arginine methyltransferase that can play roles in cancers in a highly tissue-specific manner, but its role in the carcinogenesis and metastasis of head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we detected PRMT5 expression in HNSCC tissues and performed series of in vivo and in vitro assays to investigate the function and mechanism of PRMT5 in HNSCC. We found that PRMT5 was overexpressed in dysplastic and cancer tissues, and associated with lymph node metastasis and worse patient survival. PRMT5 knockdown repressed the malignant phenotype of HNSCC cells in vitro and in vivo . PRMT5 specific inhibitor blocked the formation of precancerous lesion and HNSCC in 4NQO-induced tongue carcinogenesis model, prevented lymph node metastasis in tongue orthotopic xenograft model and inhibited cancer development in subcutaneous xenograft model and Patient-Derived tumor Xenograft (PDX) model. Mechanistically, PRMT5-catalyzed H3R2me2s promotes the enrichment of H3K4me3 in the Twist1 promoter region by recruiting WDR5, and subsequently activates the transcription of Twist1. The rescue experiments indicated that overexpressed Twist1 abrogated the inhibition of cell invasion induced by PRMT5 inhibitor. In summary, this study elucidates that PRMT5 inhibition could reduce H3K4me3-mediated Twist1 transcription and retard the carcinogenesis and metastasis of HNSCC.

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“…Previous studies have linked PRMT5 to EMT program [73][74][75] . Chen et al reported that PRMT5-MEP50 activity is required for TGFβ induced EMT by direct association with and methylation of histone substrates at EMT gene loci 18 .…”

Section: Discussionmentioning

confidence: 99%

Protein arginine methyltransferase 5 promotes metastasis via enhancing EGFR transcription and modulating AKT1 activation by methylation

Huang

Zhang

Verdejo-Torres

et al. 2020

Preprint

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Protein arginine methyltransferase 5 (PRMT5) generates most of the symmetric di-methyl-arginine marks on histones and non-histone proteins by which it regulates a wide range of physiological processes including cancer cell proliferation and metastasis. Here, we report that PRMT5 directly regulates epidermal growth factor receptor (EGFR) transcription and thus controls EGF stimulated EGFR signaling. PRMT5 modulates protein kinase B (AKT) activation by methylation of AKT1 Arg 15, which is required for its subsequent phosphorylation at AKT1 Thr 308 and Ser 473. The PRMT5/EGFR/AKT axis converges to regulate transcription factors ZEB1, SNAIL, and TWIST1 to promote the epithelial-mesenchymal transition (EMT), which supports tumor cell invasion and metastasis. Inhibiting PRMT5 methyltransferase activity with a small molecule inhibitor attenuated primary tumor growth and prevented hepatic metastasis in aggressive tumor models in vivo. Collectively, our results support the use of PRMT5 based therapies for metastatic cancer.

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PRMT5 promotes epithelial‐mesenchymal transition via EGFR‐β‐catenin axis in pancreatic cancer cells

Cited by 34 publications

References 25 publications

Hypoxia induced ferritin light chain (FTL) promoted epithelia mesenchymal transition and chemoresistance of glioma

Hypoxia induced ferritin light chain (FTL) promoted epithelia mesenchymal transition and chemoresistance of glioma

Targeting methyltransferase PRMT5 retards the carcinogenesis and metastasis of HNSCC via epigenetically inhibiting Twist1 transcription

Protein arginine methyltransferase 5 promotes metastasis via enhancing EGFR transcription and modulating AKT1 activation by methylation

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