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Restoration of TET2 deficiency inhibits tumor growth in head neck squamous cell carcinoma.

ABSTRACT: Background:Tet methylcytosine dioxygenase 2 (TET2) has been increasingly recognized as an important tumor suppressor involved in tumorigenesis. Here, we aimed to explore the expression pattern of TET2, its clinical significance as well as functional roles in head neck squamous cell carcinoma (HNSCC). Methods:Both mRNA and protein levels of TET2 in primary HNSCC samples were detected via immunohistochemistry and qRT-PCR, respectively. Correlations between TET2 expression with multiple clinicopathological parameters and patient survival were determined. The biological roles of TET2 in HNSCC were assessed via a gain-of-function approach and in 4-nitroquinoline-1-oxide (4NQO)-induced HNSCC model. Restoration of TET2 by chemicals including 5-Aza-2'-deoxycytidine (5-AZA), metformin or Vitamin C (VC) to inhibit tumor growth was determined in vitro and in a xenograft animal model. Results:Reduced TET2 expression was found in a large fraction of HNSCC samples. Downregulated TET2 significantly correlated with larger tumor size, advanced clinical stage and inferior prognosis. Reduced TET2 and 5-hydroxymethylcytosine (5hmC) were observed along with disease progression in the 4NQO-induced HNSCC model. Enforced TET2 overexpression significantly inhibited cell proliferation, migration and enhanced the chemosensitivity of cisplatin in HNSCC cells. Restoration of TET2 following 5-AZA, metformin or VC exposure impaired cell proliferation and migration in vitro. Moreover, VC alone or in synergistic with cisplatin potently inhibited tumor growth in vivo. Conclusions:Our data reveal that reduced TET2 associates with tumor aggressiveness and reduced survival in HNSCC. Genetic or pharmacological restoration of TET2 might be a viable therapeutic strategy for HNSCC patients with TET2 deficiency.

SUBMITTER: Huang R

PROVIDER: S-EPMC7186610 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Restoration of TET2 deficiency inhibits tumor growth in head neck squamous cell carcinoma.

Huang Rong R Wang Yi Y Ge Han H Wang Dongmiao D Wang Yanling Y Zhang Wei W Yang Jianrong J Cheng Jie J

Annals of translational medicine 20200301 6

<h4>Background</h4>Tet methylcytosine dioxygenase 2 (TET2) has been increasingly recognized as an important tumor suppressor involved in tumorigenesis. Here, we aimed to explore the expression pattern of TET2, its clinical significance as well as functional roles in head neck squamous cell carcinoma (HNSCC).<h4>Methods</h4>Both mRNA and protein levels of TET2 in primary HNSCC samples were detected via immunohistochemistry and qRT-PCR, respectively. Correlations between TET2 expression with multi ...[more]

PMID: 32355773

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Project description:BackgroundOverexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. Several small molecule EGFR inhibitors have been tested in clinical trials for treatment of HNSCC, but none of them are more effective than the current chemotherapeutic drugs. Thus, it is urgently needed to develop novel EGFR inhibitors for HNSCC treatment.MethodsBy screening an in-house focused library containing approximately 650 000 known kinase inhibitors and kinase inhibitor-like compounds containing common kinase inhibitor core scaffolds, we identified SKLB188 as a lead compound for inhibition of EGFR. The anticancer effects of SKLB188 on HNSCC cells were investigated by in vitro cell growth, cell cycle and apoptosis assays, as well as in vivo FaDu xenograft mouse model. Molecular docking, in vitro kinase profiling and western blotting were performed to characterise EGFR as the molecular target.ResultsSKLB188 inhibited HNSCC cell proliferation by inducing G1 cell cycle arrest, which was associated with downregulating the expression of Cdc25A, cyclins D1/A and cyclin-dependent kinases (CDK2/4), and upregulating the expression of cyclin-dependent kinase (CDK) inhibitors (p21Cip1 and p27Kip1), leading to decreased phosphorylation of Rb. SKLB188 also induced caspase-dependent apoptosis of HNSCC cells by downregulating the expression of Mcl-1 and survivin. Molecular docking revealed that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay showed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC50=5 nM). Western blot analysis demonstrated that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose-dependently inhibited FaDu xenograft growth in nude mice, and concurrently inhibited the phosphorylation of Erk1/2 and Akt in the tumours.ConclusionsSKLB188 potently inhibits the growth of HNSCC cells in vitro and in vivo by targeting EGFR signalling. The results provide a basis for further clinical investigation of SKLB188 as a targeted therapy for HNSCC. Our findings may open a new avenue for development of novel EGFR inhibitors for treatment of HNSCC and other cancers.

Project description:BackgroundMicroRNAs (miRs) are small non-coding RNAs that play an important role in cancer development where they can act as oncogenes or as tumor-suppressors. miR-34a is a tumor-suppressor that is frequently downregulated in a number of tumor types. However, little is known about the role of miR-34a in head and neck squamous cell carcinoma (HNSCC).Methods and resultsmiR-34a expression in tumor samples, HNSCC cell lines and endothelial cells was examined by real time PCR. Lipofectamine-2000 was used to transfect miR-34a in HNSCC cell lines and human endothelial cells. Cell-proliferation, migration and clonogenic survival was examined by MTT, Xcelligence system, scratch assay and colony formation assay. miR-34a effect on tumor growth and tumor angiogenesis was examined by in vivo SCID mouse xenograft model. Our results demonstrate that miR-34a is significantly downregulated in HNSCC tumors and cell lines. Ectopic expression of miR-34a in HNSCC cell lines significantly inhibited tumor cell proliferation, colony formation and migration. miR-34a overexpression also markedly downregulated E2F3 and survivin levels. Rescue experiments using microRNA resistant E2F3 isoforms suggest that miR-34a-mediated inhibition of cell proliferation and colony formation is predominantly mediated by E2F3a isoform. In addition, tumor samples from HNSCC patients showed an inverse relationship between miR-34a and survivin as well as miR-34a and E2F3 levels. Overexpression of E2F3a completely rescued survivin expression in miR-34a expressing cells, thereby suggesting that miR-34a may be regulating survivin expression via E2F3a. Ectopic expression of miR-34a also significantly inhibited tumor growth and tumor angiogenesis in a SCID mouse xenograft model. Interestingly, miR-34a inhibited tumor angiogenesis by blocking VEGF production by tumor cells as well as directly inhibiting endothelial cell functions.ConclusionsTaken together, these findings suggest that dysregulation of miR-34a expression is common in HNSCC and modulation of miR34a activity might represent a novel therapeutic strategy for the treatment of HNSCC.

Project description:BackgroundBmi1 (B lymphoma Mo-MLV insertion region 1 homolog) contributes to human tumorigenesis via epigenetic transcriptional silencing and represents a novel therapeutic target with great potentials. Here we sought to determine the therapeutic efficiency of PTC-209, a potent and selective Bmi1 inhibitor, in head neck squamous cell carcinoma (HNSCC) cells and a HNSCC xenograft model.MethodsThe mutation pattern, mRNA level of Bmi1 in HNSCC and its associations with clinicopathological parameters were determined through comprehensive data mining and interrogation using publicly available databases GENT, cBioPortal, Oncomine and TCGA. The PTC-209, a selective and potent Bmi1 inhibitor, was exploited and its effect on Bmi1 expression was measured in two HNSCC cell lines Cal27 and FaDu. The phenotypical changes of HNSCC cells were observed upon PTC-209 treatment in vitro. Moreover, the therapeutic effects of PTC-209 for HNSCC were determined in a xenograft animal model.ResultsThrough comprehensive data mining and interrogation, we found that Bmi1 mRNA was frequently overexpressed in a subset of HNSCC samples. Our data revealed that PTC-209 robustly reduced the expression of Bmi1 in Cal27 and FaDu cells presumably by post-transcriptional repression and ubiquitin-proteasomal degradation. PTC-209 treatment resulted in impaired cell proliferation, G1-phase cell cycle arrest, compromised migration and invasiveness, and increased cell apoptosis and chemosensitivity to 5-FU and cisplatin in vitro. Moreover, PTC-209 exposure reduced colony formation, tumorsphere formation and the percentage of ALDH1+ subpopulation in both Cal27 and FaDu cells. Importantly, in vivo PTC-209 administration significantly reduced tumor growth in a HNSCC xenograft model probably by Bmi1 inhibition and impaired cell proliferation.ConclusionsOur findings indicate that pharmacological inhibition of Bmi1 is a novel therapeutic strategy for HNSCC patients, especially with those with aberrant Bmi1 overexpression.

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Restoration of TET2 deficiency inhibits tumor growth in head neck squamous cell carcinoma.

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Restoration of TET2 deficiency inhibits tumor growth in head neck squamous cell carcinoma.

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