The arginine methyltransferase PRMT5 and PRMT1 distinctly regulate the degradation of anti-apoptotic protein CFLARL in human lung cancer cells

Li, Mingyue; An, Wen-Tao; Xu, Linyan; Yu, Lin; Su, Ling

doi:10.1186/s13046-019-1064-8

Cited by 40 publications

(30 citation statements)

References 48 publications

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“…However, to the best of our knowledge, only a few studies have reported the dysregulation of PRMTs in lung cancer. For example, PRMT1 and PRMT4 were identified to be involved in the regulation of proliferation in lung cancer ( 17 ); and PRMT1 and PRMT5 were discovered to regulate apoptosis induced by doxorubicin or pemetrexed by affecting cellular FADD-like IL-1β-converting enzyme-inhibitory protein in NSCLC cells ( 18 ). In addition, enolase 1 methylation by PRMT5 was discovered to be critical for lung cancer cell invasion ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

PRMT6 serves an oncogenic role in lung adenocarcinoma via regulating p18

et al. 2020

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lung adenocarcinoma (luad), a major subtype of lung cancer, is the leading cause of cancer-related mortality worldwide. Previous studies have determined the role of the protein arginine methyltransferases (PrMTs) in the physiology and pathology of luad. However, to the best of our knowledge, no empirical studies have been performed determining the association between protein arginine methyltransferase 6 (PrMT6) and luad. The present study aimed to determine the expression levels of PrMT6 in luad and its association with the clinicopathological characteristics. The effect of PrMT6 knockdown on cell growth was analyzed and chromatin immunoprecipitation (chiP) assay was used to investigate the regulatory mechanisms of PrMT6 on downstream gene expression. in addition, a xenograft model was used to determine whether the PrMT6-regulated expression levels of p18 in vitro could be validated in vivo. PrMT6 overexpression in luad is associated with high clinical stage, lymph node metastasis and poor clinical outcomes. Furthermore, the silencing of PRMT6 significantly reduced the enrichment of Histone H3 asymmetric demethylation at arginine 2 in the promoter region of the p18 gene, thereby activating the expression of the gene. This, in turn, induced G1/S phase cell cycle arrest, resulting in the inhibition of cell proliferation. The xenograft model also suggested that PrMT6 suppressed luad development by activating p18 expression in vivo. In conclusion, the findings of the present study suggested that PrMT6 may serve as an oncogene in the progression of luad through epigenetically suppressing p18 expression. Thus, PrMT6 may represent a novel potential therapeutic target for luad.

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Section: Introductionmentioning

confidence: 99%

PRMT6 serves an oncogenic role in lung adenocarcinoma via regulating p18

et al. 2020

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“…Suppression of c-FLIP expression was also found to render resistant human bladder cancer cells more sensitive to cisplatin treatment 38 . Recent studies have demonstrated PRMT1/5 to fine tune the degradation of anti-apoptotic protein CFLAR L in human lung cancer cells 39 . In this study, PRMT5 protected NSCLC cells from caspase activation and apoptosis induced by anti-cancer drugs and knocking down its expression led to CFLAR downregulation and activating chemotherapeutic-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Protein arginine methyltransferase-5 Selective Inhibitor Enhances Therapeutic Effects of Cisplatin on Lung Cancer Cells

Bajbouj¹,

Ramakrishnan²,

Saber-Ayad³

et al. 2020

Preprint

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Background Lung cancer is the most common cancer globally. Protein arginine methyltransferase 5 (PRMT5) is identified to be involved in gene transcriptional regulation and cell division. PRMT5 is highly expressed in lung adenocarcinoma, hepatocellular carcinoma, and melanoma, raising evidence that PRMT5 might be involved in tumorigenesis. The aim of this study is to examine potential selective anti-neoplastic activity of PRMT5 inhibitor, Arginine methyltransferase inhibitor 1 (AMI-1) and cisplatin on lung adenocarcinoma. Methods Effect of AMI-1 on PRMT5 activity inhibition in lung adenocarcinoma cell line, A549, in response to standard chemotherapeutic agent, cisplatin, was assessed. Bioinformatic analyses were carried out to identify the prognostic value of PRMT5 and its major functional pathways in lung adenocarcinoma. Cell viability, PMRT5 protein levels, extent of cell migration, survival of cancer cells, and cell cycle progression and apoptosis were examined. Drug combination was also evaluated in human bronchial epithelial cells (HBEpC). Results Bioinformatics identified apoptosis, DNA damage, and cell cycle progression as the main PRMT5 associated functional pathways, and survival analysis linked the increased PRMT5 gene expression to worse overall survival. Combination treatment with 10 µM AMI-1 and of Cisplatin significantly reduced viable cell percentages. Cell cycle arrest in A549 cells was evident after AMI-1, which was reinforced after combination treatment. Apoptosis was observed after treatment with both drugs. Western blot analysis showed reduction in demethylation histone 4, a PRMT5- downstream target, after treatment with AMI-1 alone or in combination with cisplatin. While combination approach tackled lung cancer cell survival, it exhibited cytoprotective abilities on normal epithelial cells. Finally, treatment with both drugs led to a decreased cell migration rate. Conclusions This study highlights evidence of novel selective antitumor additive activity of AMI-1 in combination with cisplatin in lung adenocarcinoma cells. Survival of normal bronchial epithelial cells was not affected by using AMI-1.

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“…No significant changes of these mRNAs were detected in Ptch1 +/− /Btg1 KO tumors with respect to Ptch1 +/− /Btg1 WT tumors (data not shown). Very recently, the involvement of Prmt1 in the apoptosis of tumor cells has been demonstrated, although with opposite roles in different types of cancer (59,60). Since Prmt1 is a known molecular partner of Btg1, we investigated the Prmt1 level in the MBs and we observed a significant increase of its expression in Ptch1 +/− /Btg1 KO tumors relative to Ptch1 +/− /Btg1 WT tumors (54.4% increase, p = 0.0021; Student's t-test; Figure 7A).…”

Section: B-cell Translocation Gene 1 Ablation Induces Prmt1-mediated mentioning

confidence: 99%

Deletion of Btg1 Induces Prmt1-Dependent Apoptosis and Increased Stemness in Shh-Type Medulloblastoma Cells Without Affecting Tumor Frequency

et al. 2020

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About 30% of medulloblastomas (MBs), a tumor of the cerebellum, arise from cerebellar granule cell precursors (GCPs) undergoing transformation following activation of the Sonic hedgehog (Shh) pathway. To study this process, we generated a new MB model by crossing Patched1 heterozygous (Ptch1 +/− ) mice, which develop spontaneous Shh-type MBs, with mice lacking B-cell translocation gene 1 (Btg1), a regulator of cerebellar development. In MBs developing in Ptch1 +/− mice, deletion of Btg1 does not alter tumor and lesion frequencies, nor affect the proliferation of neoplastic precursor cells. However, in both tumors and lesions arising in Ptch1 +/− mice, ablation of Btg1 increases by about 25% the apoptotic neoplastic precursor cells, as judged by positivity to activated caspase-3. Moreover, although Btg1 ablation in early postnatal GCPs, developing in the external granule cell layer, leads to a significant increase of proliferation, and decrease of differentiation, relative to wild-type, no synergy occurs with the Ptch1 +/− mutation. However, Btg1 deletion greatly increases apoptosis in postnatal GCPs, with strong synergy between Btg1-null and Ptch1 +/− mutations. That pronounced increase of apoptosis observed in Ptch1 +/− /Btg1 knockout young or neoplastic GCPs may be responsible for the lack of effect of Btg1 ablation on tumorigenesis. This increased apoptosis may be a consequence of increased expression of protein arginine methyltransferase 1 (Prmt1) protein that we observe in Btg1 knockout/Ptch1 +/− MBs. In fact, apoptotic genes, such as BAD, are targets of Prmt1. Moreover, in Btg1-null MBs, we observed a two-fold increase of cells positive to CD15, which labels tumor stem cells, raising the possibility of activation of quiescent tumor cells, known for their role in long-term resistance to treatment and relapses. Thus, Btg1 appears to play a role in cerebellar tumorigenesis by regulating the balance between apoptosis and proliferation during MB development, also influencing the number of tumor stem cells.

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The arginine methyltransferase PRMT5 and PRMT1 distinctly regulate the degradation of anti-apoptotic protein CFLARL in human lung cancer cells

Cited by 40 publications

References 48 publications

PRMT6 serves an oncogenic role in lung adenocarcinoma via regulating p18

PRMT6 serves an oncogenic role in lung adenocarcinoma via regulating p18

Protein arginine methyltransferase-5 Selective Inhibitor Enhances Therapeutic Effects of Cisplatin on Lung Cancer Cells

Deletion of Btg1 Induces Prmt1-Dependent Apoptosis and Increased Stemness in Shh-Type Medulloblastoma Cells Without Affecting Tumor Frequency

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