Role of Cell Cycle Regulators Enhancer of Zeste Homolog 2 and Cell Division Cycle 25A in Tumorigenesis of the Aerodigestive Tract

Abstract

Oral Squamous Cell Carcinoma (OSCC) and Non Small Cell Lung Cancer (NSCLC) represent the most common aerodigestive tract malignancies and are a major public health burden worldwide. The prognosis of NSCLC patients is dismal with a 5-year survival rate of 16%. Although the 5-year survival rate of patients with OSCC is more than 50%, many of the survivors suffer significant treatment side effects and disfigurement. Therefore, further understanding of the biologic basis of tumorigenic processes of these cancers is critical for development of novel diagnostic and therapeutic strategies. One of the common features of these cancers is the deregulation of cell cycle process during carcinogenesis. The transcriptional repressor Enhancer of Zeste Homolog 2 (EZH2) has been implicated in cell cycle regulation and tumorigenesis. While the cell cycle promoter Cell Division Cycle 25A (CDC25A) has been proposed as a critical cell cycle promoter linked to several malignancies. Here we investigated the role of the epigenetic EZH2 on cell cycle progression and malignant phenotypes in oral premalignancy and NSCLC. We also studied CDC25A expression and modulation of the cell cycle in NSCLC. Our results provide evidence that EZH2 promotes malignancy in Leuk-1 cell line and is a prognostic marker to OSCC onset in patients with oral premalignancy. EZH2 expression directly correlated with expression of cell cycle promoters in NSCLC NCI-H1299 and Leuk-1 cells. We also identified CDC25A-Q110del a stable isoform in NSCLC that confers CDC25A protein stability and promotes its activity. CDC25A-Q110del confers more cellular survival upon DNA damage and correlates with poor overall survival in NSCLC patients. These data unravel a novel role of EZH2 in cell cycle regulation of oral premalignancy and describe a new mode of regulation and expression of CDC25A in NSCLC. Given the potential role of the two molecules in the tumorigenic process, they may also serve as targets for blocking tumor development or progression. The link between EZH2 and CDC25A in cell cycle regulation may warrant additional investigation regarding the cross talk between the two molecules.