KBTBD7 was highly expressed in NSCLC tissues and positively correlated with the P‐TNM stage, lymph node metastasis, and tumor size.KBTBD7 enhanced ubiquitin‐dependent degradation of PTEN, thus activating EGFR/PI3K/AKT signaling and promoting NSCLC cell proliferation and invasion by regulating CCNE1, CDK4, P27, ZEB‐1, Claudin‐1, ROCK1, MMP‐9, and E‐cadherin protein levels. This evidence concerns the gene CDK4 and non-small cell lung carcinoma.