GAPDH: A common housekeeping gene with an oncogenic role in pan-cancer

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is one of the most prominent housekeeping proteins and is widely used as an internal control in some semi-quantitative assays. In addition to glycolysis, GAPDH is involved in several cancer-related biological processes and has been reported to be commonly dysregulated in multiple cancer types. Therefore, its role in the physiological process of cancer needs to be urgently elucidated. Pan-cancer analysis indicated that GAPDH is ubiquitously highly expressed in most cancer types, and that patients with a high GAPDH expression of in tumor tissues have a poor prognosis. The concordance of GAPDH expression in tumors with the infiltration of immune cells and immune checkpoints implies a certain association between GAPDH and the tumor microenvironment as well as tumor development. Gene Set Enrichment Analysis revealed that GAPDH may contribute to multiple important cancer-related pathways and biological processes. Multi-omics analysis and in vitro cell experiments revealed that GAPDH overexpression is regulated by DNA copy number amplification and promoter methylation modification. Importantly, a transcription factor, forkhead box M1 (FOXM1), which is capable of regulating GAPDH expression, was also identified and was confirmed to be an oncogene and ubiquitously highly expressed in multiple cancer types. Semi-quantitative chromatin immunoprecipitation, quantitative PCR, and dual-luciferase assays showed that FOXM1 mainly binds to the promoter region of GAPDH in two cancer cell lines. The present findings revealed the implication of GAPDH in tumor development, thus bringing attention to this important molecule and casting doubts on its role as an internal reference gene in cancer studies.