A Clinical information for HJG86 from patient’s cancer tissues. B Mice received the lentiviruses (shNT, shCDK15-3, shCDK15-7) via intratumoral injection every 3 days for a total of four times. Tumor volume was monitored every 2–5 days for four continuous weeks (n = 8 mice per group). C Tumors photographs. D Tumor weight measured at the end of the study. E Tumor growth inhibition normalized to control group. F Levels of CDK15, p-β-catenin(Ser675), c-Myc, p-MEK1/2(Ser217/221), and p-ERK1/2 (Thr202/Tyr204) in harvested tissues were assessed by immunohistochemistry. Representative photographs in different groups are shown (100×; Scale bar: 50 μm). G Statistical analysis for immunohistochemistry staining. H Schematic model for the findings of this work: Aberrant CDK15 in CRC binds PAK4 and phosphorylates PAK4 at the S291 site. Accumulated phosphorylation of S291 upregulates the β-catenin/c-Myc and MEK/ERK signals, which in turn contribute to CRC tumor growth. Statistical differences were evaluated using Student’s t-test. *P < 0.05, **P < 0.01, ***P < 0.001. Error bars represent mean ± SD.