5-Azacytidine suppresses EC9706 cell proliferation and metastasis by upregulating the expression of SOX17 and CDH1

Li, Wenli; Wu, Dan; Niu, Zi-Yu; Jiang, Dalei; Ma, Hongxia; He, Heming; Zuo, Xu; Xie, Xin; He, Yu

doi:10.3892/ijmm.2016.2704

Cited by 11 publications

(5 citation statements)

References 32 publications

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“… 15 , 40 – 42 Among the candidate tumor related new biomarkers, MrgprF, a MAS related GPR family member, was revealed to be downregulated in CM due to the hypermethylation in its promoter region, which could be reversed by 5-Azacytidine treatment, a well-known anti-cancer drug. 43 , 44 Consistently, 5-Azacytidine has previously been shown to behave as an anti-neoplastic agent for B16 melanoma. 45 , 46…”

Section: Discussionmentioning

confidence: 80%

MrgprF acts as a tumor suppressor in cutaneous melanoma by restraining PI3K/Akt signaling

Shen

Han

et al. 2022

Sig Transduct Target Ther

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The incidence of cutaneous melanoma (CM) has been increasing annually worldwide. In this study, we identify that MrgprF, a MAS related GPR family member, is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region, and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome. We demonstrate that MrgprF forced expression inhibits tumor cell proliferation, migration, xenograft tumor growth, and metastasis. On the contrary, MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells, supporting the inhibitory role of MrgprF during tumor progression. Mechanistic studies reveal that MrgprF reduces the phosphoinositol‑3‑kinase (PI3K) complex formation between p101 and p110γ subunits, the critical step for phosphatidylinositol-(3, 4)-P2 (PIP2) conversion to phosphatidylinositol-(3, 4, 5)-P3 (PIP3), and then reduces the activation of PI3K/Akt signaling. This effect can be reversed by Akt specific agonist SC79. In addition, AMG 706, a previously documented inhibitor for endothelial cell proliferation, is identified as a potential agonist for MrgprF, and can impede tumor growth both in vitro and in vivo. Taken together, our findings suggest that MrgprF, a novel tumor suppressor in cutaneous melanoma, may be useful as a therapeutic target in the future.

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Section: Discussionmentioning

confidence: 80%

MrgprF acts as a tumor suppressor in cutaneous melanoma by restraining PI3K/Akt signaling

Shen

Han

et al. 2022

Sig Transduct Target Ther

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“…Increased CDH1 expression in cancer cells reduces their ability to undergo epithelial-mesenchymal transition [30] and consequently, their metastatic potential. Interestingly, the expression of CDH1 may be activated by SOX17, as suggested in esophageal cancer cells [31]. In addition, SOX17 is also highly expressed in prostate cancer [32].…”

Section: Discussionmentioning

confidence: 88%

Effects of Red Sorghum-Derived Deoxyanthocyanidins and Their O-β-D-Glucosides on E-Cadherin Promoter Activity in PC-3 Prostate Cancer Cells

Mora,

Rosa,

Touaibia

et al. 2024

Molecules

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Although much less common than anthocyanins, 3-Deoxyanthocyanidins (3-DAs) and their glucosides can be found in cereals such as red sorghum. It is speculated that their bioavailability is higher than that of anthocyanins. Thus far, little is known regarding the therapeutic effects of 3-DAs and their O-β-D-glucosides on cancer, including prostate cancer. Thus, we evaluated their potential to decrease cell viability, to modulate the activity of transcription factors such as NFκB, CREB, and SOX, and to regulate the expression of the gene CDH1, encoding E-Cadherin. We found that 4′,7-dihydroxyflavylium chloride (P7) and the natural apigeninidin can reduce cell viability, whereas 4′,7-dihydroxyflavylium chloride (P7) and 4′-hydroxy-7-O-β-D-glucopyranosyloxyflavylium chloride (P3) increase the activities of NFkB, CREB, and SOX transcription factors, leading to the upregulation of CDH1 promoter activity in PC-3 prostate cancer cells. Thus, these compounds may contribute to the inhibition of the epithelial-to-mesenchymal transition in cancer cells and prevent the metastatic activity of more aggressive forms of androgen-resistant prostate cancer.

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“…In accordance with our study, we observed hypomethylation of DUSP5 in LUAD cells, which resulted in the upregulation of DUSP5 expression. AZA is a well-known, highly effective anticancer medication that is used to treat acute myeloid leukemia, melanoma, breast cancer, and colon cancer [75][76][77][78][79][80]. AZA promotes DNA demethylation by inhibiting DNMTs during replication, inducing silence of gene expression [81,82].…”

Section: Discussionmentioning

confidence: 99%

DUSP5 regulated by YTHDF1-mediated m6A modification promotes epithelial-mesenchymal transition and EGFR-TKI resistance via the TGF-β/Smad signaling pathway in lung adenocarcinoma

Fan,

Xing,

Yan

et al. 2024

Cancer Cell Int

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Background Lung adenocarcinoma (LUAD) patients have a dismal survival rate because of cancer metastasis and drug resistance. The study aims to identify the genes that concurrently modulate EMT, metastasis and EGFR-TKI resistance, and to investigate the underlying regulatory mechanisms. Methods Cox regression and Kaplan–Meier analyses were applied to identify prognostic oncogenes in LUAD. Gene set enrichment analysis (GSEA) was used to indicate the biological functions of the gene. Wound-healing and Transwell assays were used to detect migratory and invasive ability. EGFR-TKI sensitivity was evaluated by assessing the proliferation, clonogenic survival and metastatic capability of cancer cells with treatment with gefitinib. Methylated RNA immunoprecipitation (MeRIP) and RNA immunoprecipitation (RIP) analyses established the level of m6A modification present on the target gene and the protein’s capability to interact with RNA, respectively. Single-sample gene set enrichment (ssGSEA) algorithm used to investigate levels of immune cell infiltration. Results Our study identified dual-specificity phosphatase 5 (DUSP5) as a novel and powerful predictor of adverse outcomes for LUAD by using public datasets. Functional enrichment analysis found that DUSP5 was positively enriched in EMT and transforming growth factor-beta (TGF-β) signaling pathway, a prevailing pathway involved in the induction of EMT. As expected, DUSP5 knockdown suppressed EMT via inhibiting the canonical TGF-β/Smad signaling pathway in in vitro experiments. Consistently, knockdown of DUSP5 was first found to inhibit migratory ability and invasiveness of LUAD cells in in vitro and prevent lung metastasis in in vivo. DUSP5 knockdown re-sensitized gefitinib-resistant LUAD cells to gefitinib, accompanying reversion of EMT progress. In LUAD tissue samples, we found 14 cytosine-phosphate-guanine (CpG) sites of DUSP5 that were negatively associated with DUSP5 gene expression. Importantly, 5′Azacytidine (AZA), an FDA-approved DNA methyltransferase inhibitor, restored DUSP5 expression. Moreover, RIP experiments confirmed that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a m6A reader protein, could bind DUSP5 mRNA. YTHDF1 promoted DUSP5 expression and the malignant phenotype of LUAD cells. In addition, the DUSP5-derived genomic model revealed the two clusters with distinguishable immune features and tumor mutational burden (TMB). Conclusions Briefly, our study discovered DUSP5 which was regulated by epigenetic modification, might be a potential therapeutic target, especially in LUAD patients with acquired EGFR-TKI resistance. Graphical Abstract

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5-Azacytidine suppresses EC9706 cell proliferation and metastasis by upregulating the expression of SOX17 and CDH1

Cited by 11 publications

References 32 publications

MrgprF acts as a tumor suppressor in cutaneous melanoma by restraining PI3K/Akt signaling

MrgprF acts as a tumor suppressor in cutaneous melanoma by restraining PI3K/Akt signaling

Effects of Red Sorghum-Derived Deoxyanthocyanidins and Their O-β-D-Glucosides on E-Cadherin Promoter Activity in PC-3 Prostate Cancer Cells

DUSP5 regulated by YTHDF1-mediated m6A modification promotes epithelial-mesenchymal transition and EGFR-TKI resistance via the TGF-β/Smad signaling pathway in lung adenocarcinoma

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