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Zinc finger protein 91 (ZFP91) has been reported to be involved in various biological processes.However, the clinical significance and biological role of ZFP91 in colon cancer remains unknown.Here, we show that ZFP91 overexpression was positively associated with advanced clinical stage and poorer survival in patients with colon cancer.We found that ZFP91 upregulated HIF1α at the levels of promoter and protein in colon cancer cells.Using chromatin immunoprecipitation, electrophoretic mobility shift assay and luciferase reporter gene assay, we found that NFκB/p65 is required for the binding of ZFP91 to the HIF1α promoter at197/188 base pairs and for the transcriptional activation of HIF1α gene mediated by ZFP91.Flow cytometry, 5ethynyl2deoxyuridine(EdU) incorporation and tumor zenograft assay demonstrated that ZFP91 enhanced cell proliferation of colon cancer through upregulating HIF1 α in vitro and in vivo.Furthermore, ZFP91 is indispensable in HIF1α expression and correlated with poor prognosis in human colon cancer.Thus, we concluded that ZFP91 activates transcriptional coregulatory protein HIF1 α through transcription factor NFκB/p65 in the promotion of proliferation and tumorigenesis in colon cancer cell.ZFP91 may serve as a driver gene to activate HIF1α transcription in the development of cancer.