Dataset Information

Epigenetic silencing of CDKN1A and CDKN2B by SNHG1 promotes the cell cycle, migration and epithelial-mesenchymal transition progression of hepatocellular carcinoma.

ABSTRACT: Enhanced SNHG1 (small nucleolar RNA host gene 1) expression has been found to play a critical role in the initiation and progression of hepatocellular carcinoma (HCC) with its detailed mechanism largely unknown. In this study, we show that SNHG1 promotes the HCC progression through epigenetically silencing CDKN1A and CDKN2B in the nucleus, and competing with CDK4 mRNA for binding miR-140-5p in the cytoplasm. Using bioinformatics analyses, we found hepatocarcinogenesis is particularly associated with dysregulated expression of SNHG1 and activation of the cell cycle pathway. SNHG1 was upregulated in HCC tissues and cells, and its knockdown significantly inhibited HCC cell cycle, growth, metastasis, and epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Chromatin immunoprecipitation and RNA immunoprecipitation assays demonstrate that SNHG1 inhibit the transcription of CDKN1A and CDKN2B through enhancing EZH2 mediated-H3K27me3 in the promoter of CDKN1A and CDKN2B, thus resulting in the de-repression of the cell cycle. Dual-luciferase assay and RNA pulldown revealed that SNHG1 promotes the expression of CDK4 by competitively binding to miR-140-5p. In conclusion, we propose that SNHG1 formed a regulatory network to confer an oncogenic function in HCC and SNHG1 may serve as a potential target for HCC diagnosis and treatment.

SUBMITTER: Li B

PROVIDER: S-EPMC7532449 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Epigenetic silencing of CDKN1A and CDKN2B by SNHG1 promotes the cell cycle, migration and epithelial-mesenchymal transition progression of hepatocellular carcinoma.

Li Bei B Li Ang A You Zhen Z Xu Jingchang J Zhu Sha S

Cell death & disease 20201002 10

Enhanced SNHG1 (small nucleolar RNA host gene 1) expression has been found to play a critical role in the initiation and progression of hepatocellular carcinoma (HCC) with its detailed mechanism largely unknown. In this study, we show that SNHG1 promotes the HCC progression through epigenetically silencing CDKN1A and CDKN2B in the nucleus, and competing with CDK4 mRNA for binding miR-140-5p in the cytoplasm. Using bioinformatics analyses, we found hepatocarcinogenesis is particularly associated ...[more]

PMID: 33009370

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Project description:ObjectiveKeratin 19 (K19) expression is a potential predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). To clarify the feature of K19-proficient HCC, we traced epigenetic footprints in cultured cells and clinical materials.Patients and methodsIn vitro, KRT19 promoter methylation was analyzed and 5-aza-2'-deoxycytidine with trichostatin A (TSA) treatment was performed. Among 564 surgically resected HCCs, the clinicopathological relevance of K19-proficent HCCs was performed in comparison with hepatocytic (HepPar-1 and arginase-1), epithelial-mesenchymal transition (E-cadherin and vimentin), biliary differentiation-associated (K7 and NOTCH-1) markers, and epigenetic markers (KRT19 promoter/long interspersed nucleotide element-1 [LINE-1] methylation status).ResultsKRT19 promoter methylation was clearly associated with K19 deficiency and 5-aza-2'-deoxycytidine with TSA treatment-stimulated K19 re-expression, implicating DNA methylation as a potential epigenetic process for K19 expression. After excluding HCCs with recurrence, TNM stage as IIIB or greater, preoperative therapy, transplantation, and combined hepatocellular cholangiocarcinoma, we assessed 125 of 564 HCC cases. In this cohort, K19 expression was found in 29 HCCs (23.2%) and corresponded with poor survival following surgery (p = 0.025) and extrahepatic recurrence-free survival (p = 0.017). Compared with K19-deficient HCCs, lower KRT19 promoter methylation level was observed in K19-proficient HCCs (p < 0.0001). Conversely, HCC with genome-wide LINE-1 hypermethylation was frequently observed in K19-proficient HCCs (p = 0.0079). Additionally, K19 proficiency was associated with K7 proficiency (p = 0.043), and reduced E-cadherin and HepPar-1 expression (p = 0.043 and p < 0.0001, respectively).ConclusionsK19-proficient HCC exhibited poor prognosis owing to extrahepatic recurrence, with molecular signatures differing from those in conventional cancer stem cells, providing novel insights of the heterogeneity underlying tumor development.

Project description:The gene encoding the tumor suppressor p53 is the most frequently mutated gene in cancers. However, p53 mutation is rare in acute myeloid leukemia (AML), and p53 is inactivated predominantly by aberrant expression of p53 regulators (such as MDM2). A previous study by the authors revealed that the ZCCHC10 protein suppressed MDM2‑mediated degradation of the p53 protein in lung cancer. However, the expression and role of the ZCCHC10 gene in AML have not been investigated. In the present study, it was found that ZCCHC10 expression was downregulated in bone marrow samples of AML patients and that ZCCHC10 expression was significantly and negatively correlated with the expression of the lncRNA SNHG1. Suppression of SNHG1 decreased ZCCHC10 promoter methylation and increased ZCCHC10 expression. Notably, there is a putative binding motif in SNHG1 with full complementarity to five sites surrounding the CpG island in the ZCCHC10 promoter. Overexpression of wild‑type SNHG1 promoted ZCCHC10 methylation, but overexpression of SNHG1 with deletion of the binding motif did not. Further study identified that SNHG1 simultaneously bound to the ZCCHC10 promoter and the DNA methyltransferases DNMT1 and DNMT3B. These results indicated that SNHG1 recruits DNMT1 and DNMT3B to the ZCCHC10 promoter, resulting in hypermethylation of the ZCCHC10 promoter. Kaplan‑Meier survival analysis showed that ZCCHC10 expression was positively associated with overall survival in AML patients. In vitro experiments demonstrated that ZCCHC10 increased p53 expression and suppressed AML cell proliferation and survival. In the xenograft mouse model, ZCCHC10 decreased the proliferation of leukemic cells, improved the survival of leukemic mice, and increased sensitivity to the BCL inhibitor venetoclax. In conclusion, ZCCHC10 expression is suppressed by SNHG1‑induced DNA methylation in AML. Downregulation of ZCCHC10 decreases p53 activation, promotes cell proliferation and survival, and thereby accelerates AML progression and the acquisition of venetoclax resistance. The present study identified a SNHG1/ZCCHC10/p53 signaling axis in AML that may be a therapeutic target in this malignancy.

Dataset Information

Epigenetic silencing of CDKN1A and CDKN2B by SNHG1 promotes the cell cycle, migration and epithelial-mesenchymal transition progression of hepatocellular carcinoma.

Publications

Epigenetic silencing of CDKN1A and CDKN2B by SNHG1 promotes the cell cycle, migration and epithelial-mesenchymal transition progression of hepatocellular carcinoma.

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