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

ABSTRACT: 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.

SUBMITTER: Guo J

PROVIDER: S-EPMC7339267 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Project description:BackgroundFascin is a globular actin cross-linking protein, which plays a major role in forming parallel actin bundles in cell protrusions and is found to be associated with tumor cell invasion and metastasis in various type of cancers including oral squamous cell carcinoma (OSCC). Previously, we have demonstrated that fascin regulates actin polymerization and thereby promotes cell motility in K8-depleted OSCC cells. In the present study we have investigated the role of fascin in tumor progression of OSCC.MethodsTo understand the role of fascin in OSCC development and/or progression, fascin was overexpressed along with vector control in OSCC derived cells AW13516. The phenotype was studied using wound healing, Boyden chamber, cell adhesion, Hanging drop, soft agar and tumorigenicity assays. Further, fascin expression was examined in human OSCC samples (N = 131) using immunohistochemistry and level of its expression was correlated with clinico-pathological parameters of the patients.ResultsFascin overexpression in OSCC derived cells led to significant increase in cell migration, cell invasion and MMP-2 activity. In addition these cells demonstrated increased levels of phosphorylated AKT, ERK1/2 and JNK1/2. Our in vitro results were consistent with correlative studies of fascin expression with the clinico-pathological parameters of the OSCC patients. Fascin expression in OSCC showed statistically significant correlation with increased tumor stage (P = 0.041), increased lymph node metastasis (P = 0.001), less differentiation (P = 0.005), increased recurrence (P = 0.038) and shorter survival (P = 0.004) of the patients.ConclusionIn conclusion, our results indicate that fascin promotes tumor progression and activates AKT and MAPK pathways in OSCC-derived cells. Further, our correlative studies of fascin expression in OSCC with clinico-pathological parameters of the patients indicate that fascin may prove to be useful in prognostication and treatment of OSCC.

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

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