Mechanism Of Cdkn3 Overexpression In Cancer

The cyclin-dependent kinase inhibitor 3 (CDKN3) is a dual specificity protein tyrosine phosphatase (PTP) known to dephosphorylate CDK1/2 on the activating Thr-161/Thr-160. Paradoxically, CDKN3 mRNA is often overexpressed in human cancer. It was reported that CDKN3 overexpression may be associated with splicing variants or mutations that produce dominant-negative CDKN3. We found that CDKN3 is overexpressed in non-small cell lung cancer (NSCLC) and that CDKN3 overexpression is prognostic of poor overall survival in three cohorts of lung adenocarcinoma. We next analyzed CDKN3 transcripts in a panel of 24 cell lines and lung adenocarcinoma tissues and also examined CDKN3 mutations in the Cancer Genome Atlas (TCGA) and the Moffitt Cancer Center9s Total Cancer Care® (TCC) projects. Two CDKN3 transcripts were detected in all samples. These CDKN3 transcripts represent the full length CDKN3 mRNA and a normal transcript lacking exon 2, which encodes an out of frame 23-amino acid peptide with little homology to CDKN3. CDKN3 mutations were very rare and no disruptive mutation was found. Significantly, in synchronized cell cultures, CDKN3 mRNA and protein were elevated during the mitosis phase of cell cycle. Furthermore, CDKN3 expression had the highest correlation with mitotic-associated genes in lung adenocarcinoma tissues. Knocking down of CDKN3 prolonged the mitotic phase of cell cycle. Thus, CDKN3 overexpression in lung adenocarcinoma is not attributed to alternative splicing or mutation but is due to increased mitotic activity. Our data also suggest that CDKN3 is important for mitotic exit. Citation Format: Chao Fan, Lu Chen, Qingling Huang, Tao Shen, Eric A. Welsh, Jamie K. Teer, W Douglas Cress, Jie Wu. Mechanism of CDKN3 overexpression in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 190.