Abstract
The ING1 epigenetic regulator and tumor suppressor plays a central role in apoptosis. The Ing1 gene is functionally inactivated in many cancer types but is rarely mutated. Although most studies have implicated the major ING1 isoform, p33ING1b, in nuclear apoptotic signalling, we recently discovered a novel and potent apoptosis-inducing effect of p33ING1b translocation to the mitochondria in response to DNA damage. In the present study, we examined the impact of cytoplasmic/mitochondrial localization of p33ING1b in oral squamous cell carcinoma (OSCC) patient samples and explored the therapeutic potential of adenovirally-overexpressed p33ING1b in OSCC cell lines in combination with ionizing radiation (IR) treatment. In contrast with previous reports, we found that p33ING1b protein and mRNA levels are higher in OSCC compared to normal epithelial cells. In OSCC patient samples, higher levels of intra-tumoral cytoplasmic p33ING1b correlated with increased apoptotic markers and significantly better patient survival. This association was strongest in patients who received post-operative radiotherapy. IR treatment induced p33ING1b translocation to the mitochondria and adenoviral-p33ING1b synergized with IR to kill OSCC cells. Our results identify a novel functional relationship between cytoplasmic p33ING1b and patient survival and highlight the potential for the use of p33ING1b as a therapeutic agent in combination with adjuvant radiotherapy in OSCC.
Highlights
The Inhibitor of Growth (ING) family of tumor suppressors (ING1-5) are an evolutionarily conserved group of plant homeodomain (PHD)-containing proteins with diverse functions including chromatin remodelling, DNA damage signalling, cell cycle regulation, cellular senescence and apoptosis
Both nuclear and cytoplasmic ING1 were observed in oral squamous cell carcinoma (OSCC) (Figure 2A) and high cytoplasmic ING1 was associated with significantly improved disease-specific survival (DSS) (Figure 2B)
In contrast to previous reports, we find that Head and neck squamous cell carcinoma (HNSCC) and OSCC express higher levels of ING1 than normal squamous epithelium (Figure 1)
Summary
The Inhibitor of Growth (ING) family of tumor suppressors (ING1-5) are an evolutionarily conserved group of plant homeodomain (PHD)-containing proteins with diverse functions including chromatin remodelling, DNA damage signalling, cell cycle regulation, cellular senescence and apoptosis. The role of ING1 in genotoxic stressinduced apoptosis is suggested by the accumulation of ING1 in nucleoli and its interaction with the proliferating cell nuclear antigen (PCNA) after UV-induced DNA damage [3, 4]. The simultaneous interaction of ING1 with HDACs and H3K4Me3 results in local histone deacetylation and inhibition of transcription, leading to DNA damage signalling and apoptosis [2]. Overexpression of ING1 increases pro-apoptotic BAX and p21 protein levels, alters the mitochondrial membrane potential and induces cell cycle arrest and apoptosis [2, 8, 9]
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