Colorectal cancer (CRC) is a common malignancy globally causing significant cancer-related mortality. Recent studies have proposed p38gamma (p38 gamma) as a novel cyclin-dependent kinase (CDK)-like kinase, promoting tumorigenesis and cancer progression. The current study evaluates p38 gamma expression and potential role in CRC. In HT-29 cells and primary human colon cancer cells, shRNA-induced p38 gamma silencing or CRISPR/Cas9-mediated p38 gamma knockout inhibited cell growth, proliferation, and migration, and induced significant apoptosis. Conversely, ectopic overexpression of p38 gamma further promoted the growth, proliferation, and migration of HT-29 cells and primary colon cancer cells. Retinoblastoma (Rb) phosphorylation and cyclins (E1/A) expression were decreased by p38 gamma silencing or KO, but increased with p38 gamma overexpression. p38 gamma mRNA and protein levels are significantly upregulated in human colon cancer tissues, when compared to levels in surrounding colon epithelial tissues. These results demonstrate that overexpression of p38 gamma can promote human CRC cell progression, and identify p38 gamma as a novel therapeutic target. (C) 2019 Elsevier Inc. All rights reserved.