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Esophageal squamous cell carcinoma (ESCC) is one of the deadliest digestive tract cancer with poor prognosis. In our previous comprehensive genomics study, we identified that hotspot mutations in the solute carrier family 35 member E2 (SLC35E2) promoter region was significantly associated with worse prognosis in patients with ESCC. However, the biological function and molecular mechanism of SLC35E2 remains unclear. This study was to investigate the malignant function and mechanism of SLC35E2 in ESCC. Western blotting and qRT-PCR were used to assess the expression of SLC35E2 in ESCC cell lines. Luciferase assay and chromatin immunoprecipitation (ChIP) assay were used to assess the transcriptional inhibition of KLF4. Incucyte cell proliferation assay, colony formation assay and subcutaneous tumor formation in nude mice were used to assess the malignant function of SLC35E2. SLC35E2 can promote ESCC cell proliferation in vitro and in vivo. Krüppel-like factor 4 (KLF4), a transcriptional repressor in ESCC, binds to the SLC35E2 promoter and represses the expression of SLC35E2. The transcriptional suppression of KLF4 can be blocked by the mutation at −118 site of the SLC35E2 promoter. Besides, the accumulation of SLC35E2 expression contributes to the malignant phenotype of ESCC. These results indicate that SLC35E2 may be used as a biomarker for prognosis as well as a therapeutic target for patients with ESCC. [ABSTRACT FROM AUTHOR]