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DEPDC1 is required for cell cycle progression and motility in nasopharyngeal carcinoma.

ABSTRACT: DEP domain containing 1 (DEPDC1) is a newly identified cancer-related and cell cycle related gene and has been demonstrated as a novel therapeutic target for bladder cancer. However, the functional involvement and therapeutic potential of DEPDC1 in nasopharyngeal carcinoma (NPC) remains unclear. Our results showed that DEPDC1 was overexpressed at both mRNA and protein levels in NPC tissues compared with normal or non-tumor tissues. The siRNA-mediated DEPDC1 depletion resulted in significant inhibition of proliferation and delay in cell cycle progression in both NPC cell lines, CNE-1 and HNE-1. Detailed analysis with indirect immunofluorescence assays revealed that DEPDC1 depletion caused significant mitotic arrest accompanied with mitotic defects such as multipolar spindles and multiple nuclei followed by apoptotic cell death. Notably, DEPDC1 depletion also reduces migration and invasion ability in both cell lines. Consistent with its regulatory role in NF-κB pathway, knockdown of DEPDC1 caused significant upregulation of A20 and downregulation of mutiple NF-κB downstream target genes implicated in proliferation and tumorigenesis (c-Myc, BCL2, CCND1, CCNB1 and CCNB2), and metastasis (MMP2, MMP9, ICAM1, vimentin, Twist1). Moreover, in vivo study demonstrated that DEPDC1 knockdown also caused significant inhibition of tumor growth in the NPC xenograft nude mouse model. Taken together, our present study demonstrated that DEPDC1 is essentially required for the accelerated cell cycle progression and motility in NPC cells, and strongly suggested that DEPDC1 may serve as a novel therapeutic target in NPC.

SUBMITTER: Feng X

PROVIDER: S-EPMC5609947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CapG promoted nasopharyngeal carcinoma cell motility involving Rho motility pathway independent of ROCK.

Project description:BackgroundGelsolin-like capping actin protein (CapG) modulates actin dynamics and actin-based motility with a debatable role in tumorigenic progression. The motility-associated functions and potential molecular mechanisms of CapG in nasopharyngeal carcinoma (NPC) remain unclear.MethodsCapG expression was detected by immunohistochemistry in a cohort of NPC tissue specimens and by Western blotting assay in a variety of NPC cell lines. Loss of function and gain of function of CapG in scratch wound-healing and transwell assays were performed. Inactivation of Rac1 and ROCK with the specific small molecular inhibitors was applied to evaluate CapG's role in NPC cell motility. GTP-bound Rac1 and phosphorylated-myosin light chain 2 (p-MLC2) were measured in the ectopic CapG overexpressing cells. Finally, CapG-related gene set enrichment analysis was conducted to figure out the significant CapG-associated pathways in NPC.ResultsCapG disclosed increased level in the poorly differentiated NPC tissues and highly metastatic cells. Knockdown of CapG reduced NPC cell migration and invasion in vitro, while ectopic CapG overexpression showed the opposite effect. Ectopic overexpression of CapG compensated for the cell motility loss caused by simultaneous inactivation of ROCK and Rac1 or inactivation of ROCK alone. GTP-bound Rac1 weakened, and p-MLC2 increased in the CapG overexpressing cells. Bioinformatics analysis validated a positive correlation of CapG with Rho motility signaling, while Rac1 motility pathway showed no significant relationship.ConclusionsThe present findings highlight the contribution of CapG to NPC cell motility independent of ROCK and Rac1. CapG promotes NPC cell motility at least partly through MLC2 phosphorylation and contradicts with Rac1 activation.

| S-EPMC9580211 | biostudies-literature

NNK-mediated upregulation of DEPDC1 stimulates the progression of oral squamous cell carcinoma by inhibiting CYP27B1 expression.

Project description:Oral squamous cell carcinoma (OSCC) is a prevalent and malignant cancer. However, the molecular mechanism of OSCC progression is not fully understood. In this study, we observed that the DEP domain containing 1 (DEPDC1) protein was overexpressed in OSCC tissues and that the increased expression of DEPDC1 was closely associated with tumor size and poor clinical outcomes in OSCC patients. The results of functional investigations demonstrated that DEPDC1 stimulates OSCC cell proliferation by inhibiting cytochrome P450 family 27 subfamily B member (CYP27B1) expression. Furthermore, we observed that upregulated DEPDC1 expression was closely associated with smoking status in OSCC patients. The results of in vitro experiments showed that the tobacco compound 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) stimulates DEPDC1 expression by promoting the methylation of its gene body by increasing DNMT1 expression in OSCC cells. Notably, the silencing of DEPDC1 dramatically inhibited OSCC growth by inhibiting cell proliferation and inducing apoptosis in vivo. These findings suggest that smoking causes DEPDC1 overexpression in OSCC through DNMT1-regulated DNA methylation and that upregulated DEPDC1 stimulates OSCC cell proliferation by inhibiting CYP27B1 expression. Our results establish a new mechanism of OSCC progression and highlight DEPDC1 as a candidate prognostic biomarker and therapeutic target in OSCC.

| S-EPMC7339267 | biostudies-literature

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Overexpression of N-terminal kinase like gene promotes tumorigenicity of hepatocellular carcinoma by regulating cell cycle progression and cell motility.

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| S-EPMC3581434 | biostudies-literature

TD-60 is required for interphase cell cycle progression.

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| S-EPMC3610731 | biostudies-literature

Brevilin A Induces Cell Cycle Arrest and Apoptosis in Nasopharyngeal Carcinoma.

Project description:Nasopharyngeal carcinoma (NPC) is one of the most common malignant cancers in Southeast Asia and Southern China. Centipeda minima extract (CME) had previously demonstrated anti-cancer effects in human NPC. Brevilin A, a sesquiterpene lactone isolated from C. minima, has been reported to exhibit biological activities. In this study, we investigated its anti-NPC effect and further explored its molecular mechanisms. The effects of brevilin A were tested in the NPC cell lines CNE-1, CNE-2, SUNE-1, HONE1, and C666-1. Effects of brevilin A on cell viability were determined by MTT assay, and cell cycle and apoptosis were detected by flow cytometry. The molecular mechanism of cell cycle regulation and apoptosis were investigated via Western blot. Results showed that brevilin A inhibited NPC cell viability in a concentration- and time-dependent manner. Brevilin A induced cell cycle arrest at G2/M and induced apoptosis. Western blot results demonstrated that brevilin A could down-regulate cyclin D3, cdc2, p-PI3K, p-AKT, p-mTOR, and p-STAT3, while up-regulating cleaved PARP, cleaved caspase 9, and Bax. Regulation of cyclin B1, cdk6, and Bcl-2 expression by brevilin A showed dynamic changes according to dose and time. In the tumor xenograft model, brevilin A could reduce tumor growth, at a similar magnitude to cisplatin. However, notably, whereas cisplatin treatment led to significant weight loss in treated mice, treatment with brevilin A did not, indicating its relative lack of toxicity. Taken together, brevilin A regulated cell cycle, activated the caspase signaling pathway, and inhibited PI3K/AKT/mTOR and STAT3 signaling pathways in vitro, and exhibited similar efficacy to the common chemotherapeutic cisplatin in vivo, without its associated toxicity. These findings provide a framework for the preclinical development of brevilin A as a chemotherapeutic for NPC.

| S-EPMC6544084 | biostudies-literature

Discovery of a splicing regulator required for cell cycle progression.

Project description:In the G1 phase of the cell division cycle, eukaryotic cells prepare many of the resources necessary for a new round of growth including renewal of the transcriptional and protein synthetic capacities and building the machinery for chromosome replication. The function of G1 has an early evolutionary origin and is preserved in single and multicellular organisms, although the regulatory mechanisms conducting G1 specific functions are only understood in a few model eukaryotes. Here we describe a new G1 mutant from an ancient family of apicomplexan protozoans. Toxoplasma gondii temperature-sensitive mutant 12-109C6 conditionally arrests in the G1 phase due to a single point mutation in a novel protein containing a single RNA-recognition-motif (TgRRM1). The resulting tyrosine to asparagine amino acid change in TgRRM1 causes severe temperature instability that generates an effective null phenotype for this protein when the mutant is shifted to the restrictive temperature. Orthologs of TgRRM1 are widely conserved in diverse eukaryote lineages, and the human counterpart (RBM42) can functionally replace the missing Toxoplasma factor. Transcriptome studies demonstrate that gene expression is downregulated in the mutant at the restrictive temperature due to a severe defect in splicing that affects both cell cycle and constitutively expressed mRNAs. The interaction of TgRRM1 with factors of the tri-SNP complex (U4/U6 & U5 snRNPs) indicate this factor may be required to assemble an active spliceosome. Thus, the TgRRM1 family of proteins is an unrecognized and evolutionarily conserved class of splicing regulators. This study demonstrates investigations into diverse unicellular eukaryotes, like the Apicomplexa, have the potential to yield new insights into important mechanisms conserved across modern eukaryotic kingdoms.

| S-EPMC3578776 | biostudies-literature

Cell Division Cycle-Associated Genes Are Potential Immune Regulators in Nasopharyngeal Carcinoma.

Project description:BackgroundCell division cycle-associated (CDCA) gene family is essential to cell cycle regulation. Numerous studies have illuminated that dysfunction of CDCA genes may not only lead to uncontrolled cell proliferation resulting in tumorigenesis but also influence immune cell infiltration in tumors. However, the role of the CDCA gene family on the prognosis and immune infiltration in nasopharyngeal carcinoma (NPC) remains to be unclear.MethodsSBC human ceRNA array V1.0 was used to measure mRNA expression in three pairs of NPC tissues and nasopharyngitis tissues. The expression of CDCA8 was confirmed in an IHC microarray containing 130 NPC patients. Two external GEO cohorts were enrolled for further analysis. Prognosis analysis was performed using the Kaplan-Meier method. Gene set enrichment analysis (GSEA) was applied to explore the potential mechanism of CDCA genes in NPC. The relationship between CDCA gene family and immune infiltration in NPC was evaluated using the Xcell tool.ResultsCDCA genes were broadly upregulated in NPC tissues compared to nasopharyngitis tissues, and high expression of CDCA3/5/8 indicated worse prognosis in NPC. Besides cell cycle pathways, we found that CDCA3/5/8 were involved in multiple immune-related pathways. Overexpression of CDCA8 was strongly associated with less infiltration of CD8+ T cells and more infiltration of CD4+ Th1 cells and was negatively correlated with immune checkpoint blockade (ICB)-related genes.ConclusionCDCA gene family was upregulated in NPC, and their expressions were associated with adverse prognosis. High expression of CDCA8 was associated not only with poor prognosis, but also with less immune infiltration and downregulation of ICB-related genes in NPC.

| S-EPMC8882974 | biostudies-literature

EBV abortive lytic cycle promotes nasopharyngeal carcinoma progression through recruiting monocytes and regulating their directed differentiation.

Project description:Epstein-Barr virus (EBV) is associated with several types of human cancer including nasopharyngeal carcinoma (NPC). The activation of EBV to the lytic cycle has been observed in advanced NPC and is believed to contribute to late-stage NPC development. However, how EBV lytic cycle promotes NPC progression remains elusive. Analysis of clinical NPC samples indicated that EBV reactivation and immunosuppression were found in advanced NPC samples, as well as abnormal angiogenesis and invasiveness. To investigate the role of the EBV lytic cycle in tumor development, we established a system that consists of two NPC cell lines, respectively, in EBV abortive lytic cycle and latency. In a comparative analysis using this system, we found that the NPC cell line in EBV abortive lytic cycle exhibited the superior chemotactic capacity to recruit monocytes and polarized their differentiation toward tumor-associated macrophage (TAM)-like phenotype and away from DCs, compared to EBV-negative or EBV-latency NPC cells. EBV-encoded transcription activator ZTA is responsible for regulating monocyte chemotaxis and TAM phenotype by up-regulating the expression of GM-CSF, IL-8, and GRO-α. As a result, TAM induced by EBV abortive lytic cycle promotes NPC angiogenesis, invasion, and migration. Overall, this study elucidated the role of the EBV lytic life cycle in the late development of NPC and revealed a mechanism underlying the ZTA-mediated establishment of the tumor microenvironment (TME) that promotes NPC late-stage progression.

| S-EPMC10846743 | biostudies-literature

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