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Inhibition of the Tumor Suppressor Gene SPINK5 via EHMT2 Induces the Oral Squamous Cell Carcinoma Development

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Abstract

Serine protease inhibitor Kazal-type 5 (SPINK5) has been revealed as a significant prognostic biomarker in oral squamous cell carcinoma (OSCC). However, there is little information regarding the detailed epigenetics mechanism underlying its dysregulation in OSCC. Using the Gene Expression Omnibus database, we identified SPINK5 as a significantly downregulated gene in OSCC tissues. Moreover, SPINK5 inhibited the malignant aggressiveness of HSC3 and squamous cell carcinomas (SCC)9 cells, whereas depletion of SPINK5 using shRNAs led to the opposite trend. The euchromatic histone lysine methyltransferase 2 (EHMT2) was found to bind to the SPINK5 promoter, and EHMT2 repressed the SPINK5 expression. SPINK5 reversed the stimulating effects of EHMT2 on the aggressiveness of HSC3 and SCC9 cells by impairing the Wnt/β-catenin pathway. Wnt/β-catenin inhibitor IWR-1 treatment reverted the malignant phenotype of OSCC cells in the presence of short hairpin RNA (sh)-SPINK5. Silencing of EHMT2 inhibited tumor growth and blocked the Wnt/β-catenin signaling in OSCC, which was reversed by SPINK5 knockdown. Our study shows that SPINK5, mediated by the loss of EHMT2, can inhibit the development of OSCC by inhibiting Wnt/β-catenin signaling and may serve as a treatment target for OSCC.

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Authors and Affiliations

  1. Department of Stomatology, Ningbo First Hospital, No. 59, Liuting Street, Haishu District, Ningbo, 315000, Zhejiang, People’s Republic of China

    Suzhen Sun

  2. Department of Paediatrics, Xiantao First People’s Hospital Affiliated to Yangtze University, Xiantao, 433000, Hubei, People’s Republic of China

    Geng Su

  3. Department of Stomatology, Xiantao First People’s Hospital Affiliated to Yangtze University, Xiantao, 433000, Hubei, People’s Republic of China

    Xijiao Zheng

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Contributions

GS contributed to the conception and design of the study, data analysis, and interpretation, and also drafted and revised the manuscript. XJZ contributed to the analysis and interpretation of the data. SZS contributed to the data collection, statistical analysis, and review of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Suzhen Sun.

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Informed consent was acquired from all patients, and the study was carried out according to the World Medical Association Declaration of Helsinki. This study was approved by the Institutional Ethics Committee of Ningbo First Hospital. All animal studies were conducted under a protocol permitted by the Institutional Animal Care and Use Committee of Ningbo First Hospital following NIH guidelines for the ethical treatment of animals.

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Sun, S., Su, G. & Zheng, X. Inhibition of the Tumor Suppressor Gene SPINK5 via EHMT2 Induces the Oral Squamous Cell Carcinoma Development. Mol Biotechnol 66, 208–221 (2024). https://doi.org/10.1007/s12033-023-00740-z

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