Background:　The　upregulated　expression　of　CXCL1　has　been　validated　in　colorectal　cancer　patients.　As　a　potential　biotherapeutic　target　for　colorectal　cancer,　the　mechanism　by　which　CXCL1　affects　the　development　of　colorectal　cancer　is　not　clear.　Methods:　Expression　data　of　CXCL1　in　colorectal　cancer　were　obtained　from　the　GEO　database　and　verified　using　the　GEPIA　database　and　the　TIMER　2.0　database.　Knockout　and　overexpression　of　CXCL1　in　colorectal　cancer　cells　by　CRISPR/Cas　and　＂Sleeping　Beauty＂　transposon-mediated　gene　editing　techniques.　Cell　biological　function　was　demonstrated　by　CCK-8,　transwell　chamber　and　Colony　formation　assay.　RT-qPCR　and　Western　Blot　assays　measured　RNA　and　protein　expression.　Protein　localization　and　expression　were　measured　by　immunohistochemistry　and　immunofluorescence.　Results:　Bioinformatics　analysis　showed　significant　overexpression　of　CXCL1　in　the　colorectal　cancer　tissues　compared　to　normal　human　tissues,　and　identified　CXCL1　as　a　potential　therapeutic　target　for　colorectal　cancer.　We　demonstrate　that　CXCL1　promotes　the　proliferation　and　migration　of　colon　cancer　cells　and　has　a　facilitative　effect　on　tumor　angiogenesis.　Furthermore,　CXCL1　elevation　promoted　the　migration　of　M2-tumor　associated　macrophages　(TAMs)　while　disrupting　the　aggregation　of　CD4+　and　CD8+　T　cells　at　tumor　sites.　Mechanistic　studies　suggested　that　CXCL1　activates　the　NF-κB　pathway.　In　the　in　vivo　colon　cancer　transplantation　tumor　model,　treatment　with　the　P300　inhibitor　C646　significantly　inhibited　the　growth　of　CXCL1-overexpressing　colon　cancer.　Conclusion:　CXCL1　promotes　colon　cancer　development　through　activation　of　NF-κB/P300,　and　that　CXCL1-based　therapy　is　a　potential　novel　strategy　to　prevent　colon　cancer　development.　©　2022,　The　Author(s).