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USP13 serves as a tumor suppressor via the PTEN/AKT pathway in oral squamous cell carcinoma.

ABSTRACT: Background:: Recent studies have shown that USP13 a deubiquitinase, serves as an important regulator of tumorigenesis. However, the biological role of USP13 in oral squamous cell carcinoma (OSCC) remains enigmatic. Materials and methods:: We examined USP13 expression in OSCC and adjacent normal tissues by immunohistochemical staining. The biological functions of USP13 in OSCC cells and the possible underlying mechanisms were investigated. Results:: In this study, we showed that USP13 expression was frequently reduced in human OSCC specimens and that the reduction was correlated with the clinical stage. Functional studies demonstrated that overexpression of USP13 suppressed OSCC cell proliferation, glucose uptake and lactate production in vitro and inhibited tumor growth in vivo. Furthermore, USP13 overexpression induced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and repressed the activation of AKT as well as the expression of the downstream effectors glucose transporter-1 (GLUT1) and hexokinase-2 (HK2). Overexpression of PTEN reversed the USP13-knockdown-induced glucose uptake, lactate production, AKT activation, and expression of GLUT1 and HK2. Conclusion:: Our findings suggest that USP13 serves as a tumor suppressor by regulating the PTEN/AKT signaling pathway in OSCC cells, improving our understanding of OSCC progression and providing a clue for the development of a novel cancer therapy.

SUBMITTER: Qu Z

PROVIDER: S-EPMC6829296 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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USP13 serves as a tumor suppressor via the PTEN/AKT pathway in oral squamous cell carcinoma.

Qu Zhi Z Zhang Ran R Su Meng M Liu Weixian W

Cancer management and research 20191031

<h4>Background</h4>: Recent studies have shown that USP13 a deubiquitinase, serves as an important regulator of tumorigenesis. However, the biological role of USP13 in oral squamous cell carcinoma (OSCC) remains enigmatic.<h4>Materials and methods</h4>: We examined USP13 expression in OSCC and adjacent normal tissues by immunohistochemical staining. The biological functions of USP13 in OSCC cells and the possible underlying mechanisms were investigated.<h4>Results</h4>: In this study, we showed ...[more]

PMID: 31802942

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Project description:BACKGROUND:Oral squamous cell carcinoma (OSCC) is a genetic and epigenetic disease. There is growing evidence to suggest that environmental factors due to epigenetic changes can be involved in the OSCC pathogenesis. Although tumor suppressor genes (TSGs) are commonly inactivated by promoter hypermethylation in human cancers, the epigenetic changes and the mechanism of TSGs in human OSCC remain unclear. We therefore assessed the methylation status of the TSGs, which are associated with epigenetic silencing in human cancers, OSCC cell lines, primary tumors, and normal oral mucosa. RESULTS:We used 14 TSGs that were originally identified in colon cancer to investigate the aberrant hypermethylation of these genes associated with transcriptional silencing in 10 OSCC cell lines. We found three TSGs, TFPI2, SOX17, and GATA4, that are robustly hypermethylated and are associated with transcriptional silencing in OSCC cell lines. The re-expression of the three genes was induced by 5-aza-2'-deoxycytidine (5-aza-dC) in cells in which these genes were not expressed or had a lack of expression. In 33 cases of primary OSCC tumors, promoter hypermethylation was detected for the TFPI2, SOX17, and GATA4 genes at (32/33) 97%, (22/33) 67%, and (11/33) 33%, respectively. Eleven normal oral mucosa samples showed no promoter hypermethylation for all three genes, which suggests that this promoter hypermethylation is cancer-specific. Bisulfite sequencing analysis confirmed the cancer-specific methylation of the TFPI2, SOX17, and GATA4 promoters in the OSCC cell lines and tumors but not in the normal oral mucosa samples. More importantly, the methylation status of TFPI2, GATA4, and SOX17 was significantly associated with OSCC patients' overall survival through TCGA DNA methylation database. CONCLUSIONS:We identified that TFPI2, SOX17, and GATA4 are frequently hypermethylated in human OSCC cells in a cancer-specific manner and that the transcriptional expression of these genes is regulated by promoter hypermethylation in OSCC. Our results highlight the great potential used as a synergistic biomarker set to improve the prognosis and therapeutic treatment for patients with OSCC.

Project description:BackgroundUSP13 has been reported to be involved in the tumorigenesis of human cancers, however, its functional role and regulatory mechanisms in bladder cancer (BC) remain unclear.Methodsq-RT-PCR was performed to examine the expression of miR-130b-3p, miR-301b-3p and USP13 in BC tissue samples. Western blot, q-RT-PCR, bioinformatic analysis and dual-luciferase reporter assay were conducted to identify the regulatory function of miR-130b-3p/301b-3p for USP13. Co-immunoprecipitation assay was performed to assess the interaction between USP13 and PTEN protein. Cell-counting-kit 8, colony formation assay and transwell assay were performed to value the proliferative, migrative and invasive capacities of BC cells in vitro. Mouse xenograft model of BC cells was established to verify the function of USP13 in vivo. Immunohistochemistry was performed to identify the protein expression of USP13, NF-kB p65 or PTEN in clinical/xenograft tumor tissues.ResultsOur present study reveals that USP13 functions as a tumor suppressor by interacting with PTEN protein and increasing its expression in bladder cancer. We found that loss of USP13 led to the downregulation of PTEN and promoted proliferative, invasive and migrative capacities of bladder cancer cells. Furthermore, we discovered that USP13 was a common target of miR-130b-3p and miR-301b-3p, and the miR-130b/301b cluster, which could be transcriptionally upregulated by NF-kB. Our data demonstrated that NF-kB activation decreased expression level of USP13 and PTEN, and promoted the tumorigenesis phenotypes of BC cells. In addition, reintroduction of USP13 partially rescued PTEN expression as well as the oncogenesis trend caused by NF-kB.ConclusionWe reported a potential regulatory loop that the NF-kB-induced miR-130b/301b overexpression decreased USP13 expression and subsequently resulted in the downregulation of PTEN protein and promoted tumorigenesis of bladder cancer. Moreover, NF-kB-mediated PTEN downregulation is very likely to facilitate the full activation of NF-kB.

Dataset Information

USP13 serves as a tumor suppressor via the PTEN/AKT pathway in oral squamous cell carcinoma.

Publications

USP13 serves as a tumor suppressor via the PTEN/AKT pathway in oral squamous cell carcinoma.

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