Previous studies have shown that miR-454 plays an important role in a variety of biological processes invarious human cancer cells. However, the underlying mechanisms of this microRNA in colorectal cancer (CRC)cells remain largely unknown. In the present study, we investigated the miR-454 role in CRC cell proliferation.We found that miR-454 expression is markedly upregulated in CRC tissues and CRC cells compared with thematched tumor adjacent tissues and the FHC normal colonic cell line. Ectopic expression of miR-454 promotedthe proliferation and anchorage-independent growth of CRC cells, whereas inhibition of miR-454 reducedthis effect. Bioinformatics analysis further revealed cylindromatosis (CYLD), a putative tumor suppressoras a potential target of miR-454. Data from luciferase reporter assays showed that miR-454 directly binds tothe 3’-untranslated region (3’-UTR) of CYLD mRNA and repressed expression at both transcriptional andtranslational levels. In functional assays, CYLD-silenced in miR-454-in-transfected SW480 cells have positiveeffect to promote cell proliferation, suggesting that direct CYLD downregulation is required for miR-454-inducedCRC cell proliferation. In sum, our data provide compelling evidence that miR-454 functions as an onco-miRNA,playing a crucial role in the promoting cell proliferation in CRC, and its oncogenic effect is mediated chieflythrough direct suppression of CYLD expression.