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Manhui Xia,1,* Feng Ling,2,* Feng Gao,1 Chunmu Tao21Department of Thoracic Surgery, Jingjiang People’s Hospital of Jiangsu Province, Jingjiang City 214500, Jiangsu Province, China; 2Department of Gastroenterology, Jingjiang People’s Hospital of Jiangsu Province, Jingjiang City 214500, Jiangsu Province, China*These authors contributed equally to this workBackground: Senescence has been recognized as a mechanism for the suppression of tumorigenesis. However, how the senescence is regulated is not fully understood.Aims: The present study aims to elucidate MLL3-mediated regulation of senescence.Materials and methods: MLL3 protein levels in esophageal squamous cell carcinoma (ESCC) tissues were examined by Western blotting and immunohistochemistry. The effects of MLL3 on the growth and senescence of ESCC cells were examined using MTT assay, soft agar assay, and β-gal staining. The interaction between MLL3 and P16 was evaluated by immunoprecipitation and GST pull-down assay.Results: In this study, we found that MLL3 promoted the senescence of ESCC cells. MLL3 was downregulated in ESCC. MLL3 inhibited the growth and colony formation of ESCC cells. Mechanistically, MLL3 interacted with P16 and impaired the interaction between P16 and UHRF1 (the E3 ligase for P16), thus upregulating the protein levels of several senescence regulators.Conclusion: Collectively, this study demonstrated the regulation of senescence by MLL3.Keywords: ESCC, MLL3, senescence, P16