Q110del CDC25A : A Novel Cell Division Cycle 25A Isoform Aberrantly Expressed in Non-Small Cell Lung Cancer Rania H. Younis1, Wei Cao2, Ruxian Lin1, Ronghui Xia1,3, Zhenqiu Liu4, Martin J. Edelman5, Yuping Mei1, Li Mao 1 , Hening Ren1* 1 Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland, United States of America, 2 Department of Oral and Maxillofacial Surgery, Jiao Tong University School of Stomatology, Shanghai, China, 3 Department of Oral Pathology, 9th People Hospital, Shanghai Jiao Tong University, School of Medicine, Key Laboratory of Stomatology, Shanghai, China, 4 Department of Epidemiology, School of Medicine, University of Maryland Baltimore, Baltimore, Maryland, United States of America, 5 University of Maryland Greenebaum Cancer Center, University of Maryland Baltimore, Baltimore, Maryland, United States of America Abstract Objective: Lung cancer remains number one cause of cancer related deaths worldwide. Cell cycle deregulation plays a major role in the pathogenesis of Non-Small Cell Lung Cancer (NSCLC). CDC25A represents a critical cell cycle regulator that enhances cell cycle progression. In this study we aimed to investigate the role of a novel CDC25A transcriptional variant, CDC25AQ110del, on the regulation of the CDC25A protein, and its impact on prognosis of NSCLC patients. Methodology/Principal Findings: Here we report a novel CDC25A transcript variant with codon 110 (Glutamine) deletion, that we termed CDC25AQ110del in NSCLC cells. In 9 (75%) of the 12 NSCLC cell lines, CDC25AQ110del expression accounted for more than 20% of the CDC25A transcripts. Biological effects of CDC25AQ110del were investigated in H1299 and HEK-293F cells using UV radiation, flowcytometry, cyclohexamide treatment, and confocal microscopy. Compared to CDC25Awt, CDC25AQ110del protein had longer half-life; cells expressing CDC25AQ110del were more resistant to UV irradiation and showed more mitotic activity. Taqman-PCR was used to quantify CDC25AQ110del expression levels in 88 primary NSCLC tumor/ normal tissue pairs. In patients with NSCLC, Kaplan Meier curves showed tumors expressing higher levels of CDC25AQ110del relative to the adjacent lung tissues to have significantly inferior overall survival (P = .0018). Significance: Here we identified CDC25AQ110del as a novel transcriptional variant of CDC25A in NSCLC. The sequence- specific nature of the abnormality could be a prognostic indicator in NSCLC patients as well as a candidate target for future therapeutic strategies. Citation: Younis RH, Cao W, Lin R, Xia R, Liu Z, et al. (2012) CDC25AQ110del: A Novel Cell Division Cycle 25A Isoform Aberrantly Expressed in Non-Small Cell Lung Cancer. PLoS ONE 7(10): e46464. doi:10.1371/journal.pone.0046464 Editor: Sumitra Deb, Virginia Commonwealth University, United States of America Received June 11, 2012; Accepted August 30, 2012; Published October 5, 2012 Copyright: 2012 Younis DDS, MDS, PhD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The work was supported in part by NIH grants R01 CA126818 and R01 CA136635. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. Competing Interests: The authors have declared that no competing interests exist. * E-mail: Hren@umaryland.edu Introduction Lung cancer remains the leading cause of malignancy-related deaths worldwide despite the advances in therapeutic modalities [1]. Non-Small cell Lung Cancer (NSCLC) is the most common type of lung cancer and is a result of accumulated molecular alterations leading to deregulation of several cellular processes including cell cycle control [2]. In NSCLC, several cell-cycle regulators that play a critical role in cell cycle check point controls are altered, which allows the cancer cells bypass different checkpoints, especially at G1/S and G2/M with subsequent uncontrolled cellular proliferation [3–7]. Cell division cycle 25A (CDC25A) is a member of the CDC25 family of dual specific phosphatases and plays a critical role in cell cycle progression [8,9]. CDC25A functions to remove the inhibitory phosphates from threonine and tyrosine residues in the ATP-binding sites of CDKs, promoting cell cycle progression [10,11]. CDC25A is also a downstream target of Chk1-mediated checkpoint pathway: activation of Chk1 by DNA damaging conditions targets CDC25A for proteasome degradation, which prevents cells with chromosomal abnormalities from progressing through the cell cycle [10,12,13]. While CDK1 plays a critical role for CDC25A stabilization during mitosis [8,10,11]. CDC25A is frequently overexpressed in cancers including NSCLC. This overexpression is associated with a more aggressive clinical behavior and inferior survival [7,8,12–19]. Though CDC25A has been extensively studied for its role in tumor progression and as a potential target for cancer treatment, the mechanisms of CDC25A overexpression in cancer remains to be investigated [12]. Some studies have shown that overexpression of CDC25A in cancers could result from post-transcriptional deregulations [20] such as overexpression of DUB3 ubiquitin hydrolase [21], inactivation of glycogen synthase kinase-3beta (GSK-3beta), which phosphorylates CDC25A to promote its proteolysis in early cell- cycle phases [22], activation of LIN28A that regulates CDC25A expression by inhibiting the biogenesis of let-7 miRNA [23], and microRNA-21 which negatively regulates CDC25A, so that its PLOS ONE | www.plosone.org 1 October 2012 | Volume 7 | Issue 10 | e46464