Abstract 3153: Regulation of ATF4-mediated stress responses by NUAK2 in ovarian cancer

Abstract

Abstract NUAK family kinase 2 (NUAK2) a member of the AMPK-related serine/threonine kinase family with crucial roles in various cancer cellular processes. The aim of this study was to elucidate the expression and functions of NUAK2 in ovarian cancer while investigating the underlying molecular mechanisms. Analysis of several publicly available databases suggested a significant increase in NUAK2 mRNA levels in ovarian cancer compared to normal tissue. The overexpression of NUAK2 in ovarian cancer was confirmed by immunohistochemistry of NUAK2 in our local collection of ovarian tumor tissues comprised of carcinomas of various histological types (N=88) as well as benign and borderline tumors (N=19). Intense nuclear NUAK2 immunoreactivity was observed in serous and clear-cell carcinomas. Furthermore, nuclear expression of NUAK2 was significantly correlated with higher tumor grade and poorer overall and disease-free survival. Knocking out NUAK2 in SKOV3 cells by CRISPR-Cas9 resulted in suppressed cell growth and migration. Transcriptome by RNA sequencing and pathway enrichment analysis of SKOV3 cells overexpressing NUAK2 revealed activation of activating transcription factor 4 (ATF4) -dependent unfolded protein response (UPR) in the cell. NUAK2 knockout exaggerated the reactive oxygen species level induced by the endoplasmic reticulum (ER) stress inducer tunicamycin treatment. NUAK2 upregulated ATF4 protein expression during ER stress, facilitating its translocation into the nucleus upon exposure to tunicamycin. SKOV3 with NUAK2 knockout grew significantly slower than its parental line in mice as demonstrated by in vivo imaging. Collectively, our study highlights NUAK2 as an oncogene in ovarian cancer and underscores its involvement in the UPR pathway. Citation Format: Li Chen, Oscar GW Wong, Claire LY Cheung, Esther SY Wong, Karen KL Chan, Hextan YS Ngan, Yusanne YS Chan, Annie NY Cheung. Regulation of ATF4-mediated stress responses by NUAK2 in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3153.