The clearance of oxidative stress compounds is critical for the protection of the organism from malignancy, but how this key physiological process is regulated is not fully understood. Here, we found that the expression of GPRC5A, a well-characterized tumor suppressor in lung cancer, was elevated in colorectal cancer tissues in patients. In both cancer cell lines and a colitis-associated cancer model in mice, we found that GPRC5A deficiency reduced cell proliferation and increased cell apoptosis as well as inhibited tumorigenesis in vivo. Through RNA-Seq transcriptome analysis, we identified oxidative stress associated pathways were dysregulated. Moreover, in GPRC5A deficient cells and mouse tissues, the oxidative agents were reduced partially due to increased glutathione (GSH) level. Mechanistically, GPRC5A regulates NF-B mediated Vanin-1 expression which is the predominant enzyme for cysteamine generation. Administration of cystamine (the disulfide form of cysteamine) in GPRC5A deficient cell lines inhibited -GCS activity, leading to reduction of GSH level and increase of cell growth. Taken together, our studies suggest that GPRC5a is a potential biomarker for colon cancer and promotes tumorigenesis through stimulation of Vanin-1 expression and oxidative stress in colitis associated cancer. This study revealed an unexpected oncogenic role of GPRC5A in colorectal cancer suggesting there are complicated functional and molecular mechanism differences of this gene in distinct tissues. What's new? Colorectal cancer (CRC) is positively associated with chronic inflammation, a major feature of which is increased production of reactive oxygen species (ROS) that are capable of inducing potentially malignant changes in cells. Molecular pathways associated with those changes, however, have not been fully elucidated. Here, the retinoic acid-induced G protein-coupled receptor GPRC5A is identified as a potentially oncogenic player in CRC, whereby elevated GPRC5A expression leads to the dysregulation of pathways responsible for the clearance of oxidative agents. GPRC5A deficiency was associated with reduced cell proliferation in human cancer cell lines and with diminished tumor progression in mice.