OverlappING and DivergING roles of ING4 and ING5 in cancer, differentiation and development

The INhibitor of Growth (ING) proteins are plant homeodomain (PHD) zinc-finger epigenetic readers that recognize trimethylated lysine 4 of histone H3 (H3K4me3) and couple it to lysine-acetyltransferase (KAT) or -deacetylase (KDAC) activity on chromatin. ING4 and ING5 are among the family's closest paralogs, which share a four-domain architecture and high sequence identity, with divergence concentrated outside the PHD finger. Earlier reviews focused either on the family as a whole or on the individual INGs. This paper is the first to directly compare ING4 and ING5, including their structures, functions within KAT complexes, and roles in cancer and development, noting where they overlap and diverge. Either paralog can occupy the ING position in HBO1 (KAT7) complexes, whereas only ING5 is found in MOZ and MORF (KAT6A/B) complexes. In cancers, ING4 and ING5 generally act as tumor suppressors but can also promote malignancy and stemness. The bulk of evidence for mechanistically explaining the effects of ING4/5 in cancers comes from ectopic overexpression studies. In differentiation, ING5 has been investigated far more than ING4, and the roles of the two mostly diverge: ING5 participates in maintaining stemness in neural, epidermal, and brain tumor initiating cell lines, as well as proliferation of mesenchymal stem cells, whereas ING4 was found to restrain hematopoietic stem cell self-renewal, promote prostate epithelial differentiation, but promote stemness of renal cell carcinoma cells. They nonetheless compensate for one another in embryonic survival, since either paralog alone prevents the arrest seen in double knockouts. The key remaining questions include what determines the structural basis of ING5's MOZ/MORF selectivity, what the precise conditions are under which they substitute for one another, how exactly ING4 and ING5 can be targeted in cancer therapy, and whether the roles of the two paralogs are conserved across species.