Inhibitor of growth tumor suppressors in cancer progression

Abstract

The inhibitor of growth (ING) family of tumor suppressors has five members and is implicated in the control of apoptosis, senescence, DNA repair, and cancer progression. However, little is known about ING activity in the regulation of cancer progression. ING members and splice variants seem to behave differently with respect to cancer invasion and metastasis. Interaction with histone trimethylated at lysine 4 (H3K4me3), hypoxia inducible factor-1 (HIF-1), p53, and nuclear factor kappa-B (NF-kappaB) are potential mechanisms by which ING members exert effects on invasion and metastasis. Subcellular mislocalization, rapid protein degradation, and to a lesser extent ING gene mutation are among the mechanisms responsible for inappropriate ING levels in cancer cells. The aim of this review is to summarize the different roles of ING family tumor suppressors in cancer progression and the molecular mechanisms involved.

Fig. 1

Potential mechanisms for ING transcriptional regulation of genes involved in cancer progression. a ING2 interacts with PCNA during DNA replication, allowing normal cell proliferation to maintain genomic stability. b In colon cancer, NF-κB binds to the ING2 promoter regulatory region, increasing the expression of ING2. ING2 recruits mSin3a to the MMP-13 promoter and binds to H3K4me3 resulting in MMP-13 transcriptional activation. c ING4 binds to NF-κB at the promoter of NF-κB-regulated genes and suppresses NF-κB activity via reducing H3K4me3 and inhibiting NF-κB p65 phosphorylation. ING4 decreases p65–p300 interaction in favor of HDAC-1 recruitment. d During hypoxia, ING4 interacts with the prolyl hydroxylase and recruits chromatin-remodeling factors to HIF target gene promoters, suppressing HIF-1-regulated gene expression