Abstract LB-301: MicroRNA target screen identifies NEK9 pathway as a crucial component regulating proliferation of cancer cells lacking functional p53

Abstract

Abstract An abnormality of TP53 is one of the hallmarks of human cancer, and a major cause of human cancer development. Therefore, selective elimination of p53-inactivated cancer cells represents an ideal therapeutic strategy. We previously identified miR-22 as a tumor-suppressive miRNA, which induces apoptosis in p53 wild type (WT) cancer cells, but it causes cell cycle arrest in p53-deficient cancer cells (Cancer Res. 2011). This finding led us to hypothesize that miR-22 has a unique set of target genes that determined the fate of cancer cells according to p53 mutation status. In this study, using miR-22 as a screening tool, we tried to identify factors that play important roles in proliferation and cell cycle progression of p53-inactivated cancer cells. The screen identified NIMA-related kinase 9 (NEK9) as such a crucial regulator. Both in vitro and in vivo, depletion of NEK9 selectively inhibited cell proliferation of p53-inactivated cancer cells, and expression of the NEK9 open reading frame restored proliferation. The resultant cell cycle arrest occurred pre-dominantly in G1 phase and exhibited features of pre-mature senescence. Furthermore, repression of NEK9 affected expression of a wide range of genes encoding factors involved in mRNA processing, receptor signaling and cell cycle regulation, suggesting that NEK9 plays a role in controlling these processes in p53-deficient cells. Importantly, high level expression of both NEK9 and p53 mutant proteins in lung adenocarcinoma specimens were associated with poor prognosis, suggesting that NEK9 confers some advantages for malignant progression of p53 mutant cancer. Collectively, our findings indicated that a novel NEK9 network, which is specifically activated in p53-deficient context, is a crucial cellular component responsible for the growth capacity of cancer cells lacking functional p53. Citation Format: Naoto Tsuchiya. MicroRNA target screen identifies NEK9 pathway as a crucial component regulating proliferation of cancer cells lacking functional p53. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-301. doi:10.1158/1538-7445.AM2015-LB-301