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MDM2-P53 Signaling Pathway-Mediated Upregulation of CDC20 Promotes Progression of Human Diffuse Large B-Cell Lymphoma.

ABSTRACT: Background:Cell-division cycle 20 (CDC20) is overexpressed in a variety of tumor cells and is negatively regulated by wild-type p53 (wtp53). Our previous study uncovered that CDC20 was upregulated and associated with poor outcome in diffuse large B-cell lymphoma (DLBCL) based on bioinformatics analysis. Dysregulation of the MDM2-p53 is a major mechanism to promote DLBCL. Thus, we hypothesized that CDC20 could be a downstream gene of the MDM2-p53 signaling pathway. However, the clinical significance and mechanistic role of a novel MDM2-p53-CDC20 signaling pathway in DLBCL have still remained unclear. Materials and Methods:RT-qPCR was performed in MDM2 knocked down (KD) and control (Ctrl) OCI-Ly3/OCI-Ly10 cells to investigate whether CDC20 was a downstream gene of the MDM2-p53 pathway. The effects of CDC20 on cell proliferation, cell cycle and apoptosis were assessed, as well as the role of CDC20 in suppressing tumorigenicity in vivo. Furthermore, we also investigated the roles of CDC20 and MDM2 in progression of DLBCL and the underlying mechanisms. Results:The results of RT-qPCR revealed that CDC20 was downregulated while TP53 was upregulated in MDM2 KD OCI-Ly3 and OCI-Ly10 cells. It was unveiled that the expression levels of CDC20 and MDM2 were upregulated in DLBCL tissues and cells, and high CDC20 expression was correlated with adverse clinical features and poor outcome. Functional assays showed that downregulation of CDC20 could inhibit proliferation, induce apoptosis and cell cycle arrest in vitro. In addition, inactivation of the MDM2-p53 pathway by downregulation of MDM2 restored wtp53 expression level and reduced CDC20 protein level in OCI-Ly3 and OCI-Ly10 cells. Besides, targeting CDC20 was found to suppress tumorigenesis of DLBCL in vivo. Conclusion:CDC20 was identified as a key downstream gene of the MDM2-p53 signaling pathway in DLBCL and may be used as a novel target gene to guide therapeutic applications.

SUBMITTER: Sun C

PROVIDER: S-EPMC7575066 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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MDM2-P53 Signaling Pathway-Mediated Upregulation of CDC20 Promotes Progression of Human Diffuse Large B-Cell Lymphoma.

Sun Chengtao C Li Mengzhen M Feng Yanfen Y Sun Feifei F Zhang Li L Xu Yanjie Y Lu Suying S Zhu Jia J Huang Junting J Wang Juan J Hu Yang Y Zhang Yizhuo Y

OncoTargets and therapy 20201015

<h4>Background</h4>Cell-division cycle 20 (CDC20) is overexpressed in a variety of tumor cells and is negatively regulated by wild-type p53 (wtp53). Our previous study uncovered that CDC20 was upregulated and associated with poor outcome in diffuse large B-cell lymphoma (DLBCL) based on bioinformatics analysis. Dysregulation of the MDM2-p53 is a major mechanism to promote DLBCL. Thus, we hypothesized that CDC20 could be a downstream gene of the MDM2-p53 signaling pathway. However, the clinical s ...[more]

PMID: 33116627

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Project description:BackgroundN6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined.MethodsThe expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments.ResultsDysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo-YAP signaling, reprogramming the expression of Hippo target genes.ConclusionsOur results revealed a new mechanism by which the Hippo-YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression.

Project description:Objectivep53 gene, as "the guardian of the genome", is the most widely studied tumor suppressor gene. Previous studies have shown that about 50 percent of tumors have P53 dysfunction. This article aims to retrospectively analyze the correlation between p53 rs1625895 polymorphism and the prognosis of patients with diffuse large B-cell lymphoma (DLBCL).MethodsPCR combined with Sanger sequencing were used to detect rs1625895 genotype in 384 DLBCL patients. The relationship between rs1625895 polymorphisms and the clinical characteristics, first-line therapeutic effects and the prognosis of the patients were analyzed.ResultsAmong all the patients, 2 (0.5%) patients with AA genotype, 34 (8.9%) patients with AG genotype and 348 (90.6%) patients with GG genotype were identified. The patients with different rs1625895 genotypes did not have any difference in terms of age, gender, B symptoms (developing any of the following symptoms: unexplained recurrent fever (often above 38 °C), night sweats, and unexplained weight loss of 10% within 6 months ), erythrocyte sedimentation rate (ESR), international prognostic index (IPI) and molecular subtype (P>0.05). The overall response rate (ORR) was 82.9% and 82.8% in AA/AG and GG, respectively. There was no significant difference between the first-line therapeutic effects of the two groups (P>0.05). And there was also no difference between A allele carriers and homozygous G allele carriers for the 5-year progressionfree survival rate (PFS) (71.8% vs. 62.3%, χ2=1.351, P=0.245) and 5-year overall survival rate (OS) (72.2% vs. 64.1%, χ2=1.267, P=0.260). But in the subgroup with Germinal Center B-cell (GCB) type, the patients carrying A allele for rs1625895 had an obviously longer PFS (91.7% vs. 72.7%, χ2=4.493, P=0.034) and OS (91.7% vs. 76.7%, χ2=4.246, P=0.039) compared with the patients homozygous for the G allele. As for the patients with non-GCB subtype, there was no significant difference in PFS and OS between different rs1625895 genotypes (P>0.05). According to whether the first-line regimen contained rituximab or not, the patients were divided into two groups treated with cyclophosphoramide, doxorubicin, vincristine and prednisone (CHOP) or with rituximab and CHOP (R-CHOP). But in both subgroups, there was no significant difference in the 5-year PFS and OS between the AA/AG and GG patients, too (P>0.05).ConclusionFor DLBCL patients receiving CHOP regimen chemotherapy in the first line, p53 rs1625895 cannot predict the clinical efficacy and prognosis of the patients, but in the patients with GCB subtype, this polymorphism may be a prognostic indicator.

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MDM2-P53 Signaling Pathway-Mediated Upregulation of CDC20 Promotes Progression of Human Diffuse Large B-Cell Lymphoma.

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MDM2-P53 Signaling Pathway-Mediated Upregulation of CDC20 Promotes Progression of Human Diffuse Large B-Cell Lymphoma.

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