ING Genes Work as Tumor Suppressor Genes in the Carcinogenesis of Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world. The evolution and progression of HNSCC are considered to result from multiple stepwise alterations of cellular and molecular pathways in squamous epithelium. Recently, inhibitor of growth gene (ING) family consisting of five genes, ING1 to ING5, was identified as a new tumor suppressor gene family that was implicated in the downregulation of cell cycle and chromatin remodeling. In contrast, it has been shown that ING1 and ING2 play an oncogenic role in some cancers, this situation being similar to TGF-β. In HNSCC, the ING family has been reported to be downregulated, and ING translocation from the nucleus to the cytoplasm may be a critical event for carcinogenesis. In this paper, we describe our recent results and briefly summarize current knowledge regarding the biologic functions of ING in HNSCC.

Figure 1

Structure of ING proteins in Homo sapiens. Each ING protein with its name and encoding major variants is listed on the left. The characterized domain composition, approximate location, is shown on the right. All ING proteins contain three conserved regions, a PHD (plant homeodomain), NLS (nuclear localization signal), and NCR (novel conserved region) from C-terminal region to N-terminal region. An LZL (leucine zipper-like domain) is present in ING2-5. p33^ING1b also have a PIP (PCNA-Interacting Protein Motif) domain through which it binds to PCNA following UV irradiation, a PBD (partial bromodomain) which commonly found in chromatin-associated protein, and an LID (Lamin Interaction domain). p33^ING1b binds to lamin A/HDAC complexes via LID to maintain its levels and biological function in nucleus. Additionally, phosphorylation sites were found at serine 199 of p33^ING1b. 14-3-3 bind to phosphorylated serine 199 result in translocation of p33^ING1b from the nucleus to the cytoplasm.

Figure 2

The role of p33^ING1b protein in tumor supression. p33^ING1b could recognize trimethylated lysine 4 of histone H3 (H3K4me3) by PHD domain and has been implicated in chromatin remodeling and activation of some genes transcription. This binding is somehow necessary for induction of DNA repair and cell death. p33^ING1b also associates with the Sin3/HDAC-mediated transcriptional repression through its unique N-terminal sequence and may be involved in repression of some essential cell cycle regulator genes. Moreover, p33^ING1b binds PCNA and p300 complex to promote DNA repair through a PIP motif in response to UV-irradiation and, subsequently, may trigger apoptosis by the induction of p21 expression. p33^ING1b competes with murine double minute 2 (MDM2) leading to an increase in the stability and activity of p53. p21, the one of the targets of p53, is also upregulated to involve in cell cycle arrest and the induction of apoptosis. Additionally, p33^ING1b could upregulate expression of HSP70 gene to induce apoptosis independently of p53 status. Furthermore, p33^ING1b binds to lamin A via LID domain to stabilize its level and biological function in nucleus. Conversely, 14-3-3 can bind to p33^ING1b with phosphorylated serine 199 and results in translocation of p33^ING1b from the nucleus to the cytoplasm, which may involve in tumorigenesis.

Figure 3

The schematic diagram of ING proteins expression in the malignant development of HNSCC. Nuclear expression of ING proteins is downregulated from normal squamous epithelium to dysplastic epithelium and invasive HNSCC. In contrast, the cytoplasmic expression of ING proteins in dysplastic epithelium and invasive HNSCC is gradually increased compared with normal squamous epithelium. The positive expression of ING proteins is shown with brown color.