The Inhibitor of Growth (ING) Gene Family: Potential Role in Cancer Therapy

Abstract

The discovery of ING1 gene paved the way to the identification of other ING members (ING2-5) and their isoforms associated with cell cycle, apoptosis and senescence. The ING family has been an emerging putative tumor suppressor gene (TSG) in which the major mechanism is through interaction with the determinants of chromatin function and gene-specific transcription factors. The regulatory mechanism highly involves the conserved plant homeodomain (PHD), which binds to histones in a methylation-sensitive manner, suggesting that ING proteins may contribute to the maintenance of the epigenetic code. Furthermore, ING family members contain nuclear localization signals and N-terminal sequences important in the interaction with histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) that regulate gene promoter activity within chromatin. Although ING proteins have the same PHD motif, the variation in the N-terminal dictates the differences in tumor the suppressive ability of ING in various tumors. Inactivation of the normal function is achieved through allelic loss of genomic regions containing the ING gene, alteration in the ING promoter region, variation of mRNA splicing efficacy or reduced mRNA stability. It is most probably the apparent combination of these aberrant mechanisms that resulted in reduced availability of functional ING protein. In cancer cells, ING transcript levels are often suppressed but the genes are rarely mutated. The mechanism of suppression of ING expression may have to do with the abnormally high methylation levels of the ING gene promoter, which have been correlated with low transcript levels. Emerging evidence on the function of ING and related regulatory mechanisms strongly points to ING as a candidate TSG and therefore a potential target in the molecular therapy of some types of tumor.

Epigenetic Profiling of Oral Cancer

“…Recently, the potential roles of ING proteins as prognostic biomarkers, detector of aggressive behavior of tumors as well as predictive factor of chemoradiotherapy response, have been hypothesized. Emerging evidence on the function of ING and related regulatory mechanisms strongly points to ING as a candidate TSG and therefore a potential target in the molecular therapy of some types of cancer Demircan, K., 2009;Rivera, R.S., 2008). Being research on INGs in its early stages, this topic will not be treated in this chapter.…”

Role of ING Family Genes in Head and Neck Cancer and Their Possible Applications in Cancer Diagnosis and Treatment

“…Thus this review will mainly include alterations of ING family tumor suppressor in human cancer and their possible applications in molecular diagnosis and therapy of cancer. The five members of the ING family were recently identified by our group and other researchers in the field [11][12][13][14][15][16][17]. All proteins of ING family genes contain a highly conserved plant homeodomain (PHD) finger motif in the carboxy (C)-terminal end that is commonly detected in various chromatin remodeling proteins [18,19].…”

“…All proteins of ING family genes contain a highly conserved plant homeodomain (PHD) finger motif in the carboxy (C)-terminal end that is commonly detected in various chromatin remodeling proteins [18,19]. The N-terminal part of each ING protein seems to be unique, which determines the structure and different functions of various ING genes [11,12,16]. Although exact functions of ING family genes h a v e n o t b e e n c l a r i f i e d , t h e g e n e p r o d u c t s h a v e b e e n r e p o r t e d t o b e i n v o l v e d i n transcriptional regulation, apoptosis, cell cycle, angiogenesis and DNA repair through p53-dependent and -independent pathways.…”

“…Although exact functions of ING family genes h a v e n o t b e e n c l a r i f i e d , t h e g e n e p r o d u c t s h a v e b e e n r e p o r t e d t o b e i n v o l v e d i n transcriptional regulation, apoptosis, cell cycle, angiogenesis and DNA repair through p53-dependent and -independent pathways. Moreover, ING family genes have also been known to constitute complexes with histone acetyltransferases (HAT) and histone deacetylases (HDAC) [11,12,16,20].…”

“…These randomly fragmented cDNAs interfered with the activity of tumor suppressors by either blocking protein production through anti-sense sequences or abrogating function in a dominant-negative fashion through truncated sense fragments [21]. The other four members of ING gene family have been identified through sequence homologies with ING1, followed by functional in-vitro and then in-vivo cancer patient tissue analysis [11,12,19,22,23].…”