Abstract
Inhibitor of growth 4 (ING4), a member of the ING family discovered in 2003, has been shown to act as a tumor suppressor and is frequently down-regulated in various human cancers. Numerous published in vivo and in vitro studies have shown that ING4 is responsible for important cancer hallmarks such as pathologic cell cycle arrest, apoptosis, autophagy, contact inhibition, and hypoxic adaptation, and also affects tumor angiogenesis, invasion, and metastasis. These characteristics are typically associated with regulation through chromatin acetylation by binding histone H3 trimethylated at lysine 4 (H3K4me3) and through transcriptional activity of transcription factor P53 and NF-κB. In addition, emerging evidence has indicated that abnormalities in ING4 expression and function play key roles in non-neoplastic disorders. Here, we provide an overview of ING4-modulated chromosome remodeling and transcriptional function, as well as the functional consequences of different genetic variants. We also present the current understanding concerning the role of ING4 in the development of neoplastic and non-neoplastic diseases. These studies offer inspiration for pursuing novel therapeutics for various cancers.
Highlights
Tumor suppressor genes (TSGs) can oppose oncogene function and restrain cancer development, with inactivation of tumor suppressor gene (TSG) being essential for cancer development, along with the aberrant activation of oncogenes [1]
Inhibitor of growth 4 (ING4) suppresses tumor invasion and metastasis via reversal of Epithelial–mesenchymal transition (EMT) through down-regulation of Snail1 and through a switch from N-cadherin to E-cadherin [79], principally by targetting the Wnt/β catenin signaling pathway [109]. These findings indicate that ING4 may promote metastasis by regulating metastasis-associated genes, such as those encoding matrix metalloproteinase (MMP)
Considering the complex mechanisms implicated in this process, we suggest that ING4 is likely to trigger multiple signaling pathways through chromatin remodeling and binding to diverse sets of proteins simultaneously
Summary
Tumor suppressor genes (TSGs) can oppose oncogene function and restrain cancer development, with inactivation of TSGs being essential for cancer development, along with the aberrant activation of oncogenes [1]. Garkavtsev et al [55] initially revealed that ING4 physically interacts with the p65/RelA subunit of NF-κB, forming a transcriptional complex that represses NF-κB-responsive genes such as interleukin (IL) 6 (IL-6), IL-8, cox-2, and CSF-3 in human glioblastoma U87MG cells. In this way, ING4 affects tumor angiogenesis and directly influences brain tumor growth [55]. The ING4 protein level has been shown to correlate with vein invasion and
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