Integrated genomic analyses identify KDM1A's role in cell proliferation via modulating E2F signaling activity and associate with poor clinical outcome in oral cancer

• Published in: Cancer letters 2015-10, Vol.367 (2), p.162-172
• Main Authors: Narayanan, Sathiya Pandi, Singh, Smriti, Gupta, Amit, Yadav, Sandhya, Singh, Shree Ram, Shukla, Sanjeev
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Line, Tumor; Cell Proliferation; Computer Simulation; E2F1 signaling; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genetic Association Studies; Histone demethylase; Histone Demethylases - genetics; Histone Demethylases - metabolism; Humans; KDM1A; Mouth Neoplasms - enzymology; Mouth Neoplasms - genetics; Mouth Neoplasms - mortality; Mouth Neoplasms - pathology; Oral cancer; Phenotype; Prognosis; Proportional Hazards Models; RNA Interference; RNA, Messenger - metabolism; Signal Transduction; Time Factors; Transfection; Up-Regulation
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2015.07.022

•Oral cancer is the sixth most common cancer in the developing countries.•Elevated expression of KDM1A in oral cancers promotes cell proliferation.•KDM1A knockdown decreases E2F signaling in oral cancer cell lines.•KDM1A promotes cell proliferation via modulating E2F signaling.•Elevated KDM1A expression is associated with poor clinical outcome in oral cancer. The histone demethylase KDM1A specifically demethylates lysine residues and its deregulation has been implicated in the initiation and progression of various cancers. However, KDM1A's molecular role and its pathological consequences, and prognostic significance in oral cancer remain less understood. In the present study, we sought to investigate the expression of KDM1A and its downstream role in oral cancer pathogenesis. By comparing mRNA expression profiles, we identified an elevated KDM1A expression in oral tumors when compared to normal oral tissues. In silico pathway prediction identified the association between KDM1A and E2F1 signaling in oral cancer. Pathway scanning, functional annotation analysis and In vitro assays showed the KDM1A's involvement in oral cancer cell proliferation and the cell cycle. Moreover, real time PCR and luciferase assays confirmed KDM1A's role in regulation of E2F1 signaling activity in oral cancer. Elevated KDM1A expression is associated with poor clinical outcome in oral cancer. Our data indicate that deregulated KDM1A expression is positively associated with proliferative phenotype of oral cancer and confers poor clinical outcome. These cumulative data suggest that KDM1A might be a potential diagnostic and therapeutic target for oral cancer.