Lung　cancer　has　been　notorious　for　its　lack　of　advance　in　clinical　therapy,　urging　for　effective　therapeutic　targets.　WD　repeat-containing　protein　74　(WDR74)　has　previously　been　implicated　in　tumorigenesis,　but　its　mechanistic　functions　remain　not　well　understood.　Herein,　WDR74　expression　was　observed　to　be　increased　upon　lung　cancer　progression　from　healthy　normal　tissues　to　the　primary　cancer　and　further　to　the　metastatic　cancer.　Through　gain-　and　loss-of-function　approaches,　we　found　that　WDR74　regulated　lung　cancer　cell　proliferation,　cell　cycle　progression,　chemoresistance　and　cell　aggressiveness　in　vitro.　Moreover,　a　xenograft　mouse　model　disclosed　that　WDR74　knockout　inhibited　lung　cancer　growth　and　metastasis,　whereas　WDR74　overexpression　reciprocally　enhanced　these　characteristics.　Mechanistically,　WDR74　promoted　nuclear　β-catenin　accumulation　and　drove　downstream　Wnt-responsive　genes,　thus　revealing　that　WDR74　activated　the　Wnt/β-catenin　signaling　pathway.　Collectively,　WDR74　inducing　nuclear　β-catenin　accumulation　and　driving　the　downstream　Wnt-responsive　genes　expression　facilitates　lung　cancer　growth　and　metastasis.　WDR74　can　serve　as　a　candidate　target　for　the　prevention　and　treatment　of　lung　cancer　in　clinic.　©　2019