CtBP: A mediator of a metabolic switch from homeostasis to carcinogenesis

The dimeric form of C-terminus binding protein (CtBP), which is responsible for a balanced transcription rate of genes involved in the homeostatic processes, is a global corepressor. CtBP dimerization and formation of the CtBP corepressor complex require NADH. Under a normal NADH/NAD+ ratio, CtBP is in the dimeric form while, when NADH/NAD+ decreases, it converts into a monomeric form. The monomeric form of CtBP inhibits histone acetyltransferase p300, which plays an important role in the packaging of newly replicated and repaired DNA into chromatin by acetylating the histone H3 core domain lysine 56 (H3K56). Further, by inhibiting p300, the monomeric form of CtBP inhibits NFκB, which plays an important role in the innate immune response toward neoantigens. Furthermore, NFκB causes the transcription of IL-6, which is important in the resolution of the innate immune response. Moreover, by inhibiting p300, the monomeric CtBP inhibits p53, the guardian of the genome. Thus, by inhibiting p300, the monomeric form of CtBP may be involved in carcinogenesis when NADH/NAD+ ratio decreases. In contrast, hypoxia increases the NADH/NAD+ ratio, generating the dimeric form of CtBP and relieving the inhibition of p300 by the monomeric CtBP. The higher NADH/NAD+ ratio and p300 activity under hypoxia mask the instability of cancer cells, confer invasive properties, cause COX-2 expression, increase the transactivation activity of the hypoxia-inducible factor (HIF), and cause drug resistance through NFκB. Thus, p300, regulated by NADH/NAD+ ratio through CtBP, works as a double-edged sword in cancer initiation and progression, respectively. • A decrease in the NADH/NAD+ ratio generates the monomeric form of CtBP. • The monomeric form of CtBP causes cell proliferation. • The monomeric form of CtBP causes genomic instability and carcinogenesis. • The dimeric form of CtBP causes the progression of cancer through p300. • Hypoxia increases the NADH/NAD+ ratio, producing the dimeric form of CtBP which increases the stability of cancer cells. • Normalization of the tumor microenvironment and a simultaneous increase in NADH/NAD+ ratio in the human body may be a promising strategy for cancer treatment.