Abstract 5680: Hypoxia-responsive and HIF1α-regulated AAA+ ATPase ATAD2 shows high oncogenic potential in stomach cancer

Abstract The burden of stomach cancer incidence and death is a global challenge. Treating stomach cancer remains immensely difficult due to the lack of available markers to detect the disease at the early stages. Therefore, there is an immense demand for finding out an early detection biomarker for stomach cancer. Recently, ATAD2 is found to be overexpressed in stomach cancer with high prognostic significance and recognised as a promising biomarker for stomach cancer. ATAD2 is a unique cancer/testis antigen (CTA) that belongs to both AAA+ ATPase and bromodomain family proteins. However, nothing much is known about the mechanism of ATAD2-mediated stomach carcinogenesis. Using bioinformatics analyses as well as studies with stomach cancer cells and stomach biopsy tissue samples, we address the regulation and function of ATAD2 expression in stomach cancer. We show that ATAD2 is overexpressed in the most common intestinal type of stomach adenocarcinoma, and enhanced expression of ATAD2 is observed in all stages and grades of stomach cancer. Our immunofluorescence microscopy study with stomach biopsy tissues confirms the high expression of ATAD2 both in stomach adenocarcinoma and metastatic stomach tissue samples. Survival analysis indicates that upregulated ATAD2 expression drastically affects the survival of stomach cancer patients. Since H. pylori infection, and hypoxia are the major contributing factors for stomach carcinogenesis; we further study their role in ATAD2-mediated stomach malignancy. An enhanced expression of ATAD2 is observed in H. pylori-infected stomach cancer cells. We identify ATAD2 as a hypoxia-responsive and HIF1α-regulated gene and elucidate that upregulated expression of ATAD2 enhances proliferation and migration of hypoxic stomach cancer cells. We further recognize the protein-protein interaction (PPI) network of ATAD2 with the top-ranked partners like ESR1 (or ERα), NCOA3 (or ACTR/SRC3/AIB1), SUMO2, HDA11 (HDAC11), SPTN2 (SPTBN2), and MYC. Among them, ESR1, MYC, NCOA3, and HDA11 are oncoproteins. Most strikingly, we report the participation of two druggable targets of ATAD2, i.e., AAA+ ATPase and bromodomain in the ATAD2-PPI network; ESR1, SUMO2, SPTN2, and MYC show a preference for bromodomain, whereas NCOA3 and HDA11 prefer ATPase domain of ATAD2. The importance of such findings in terms of targeting bromodomain-PPI and/or ATPase-PPI interfaces to curtail stomach cancer is elucidated. Citation Format: Anasuya Roychowdhury, Aditi Nayak, Sugandh Kumar, Anshuman Dixit, Asima Bhattacharyya. Hypoxia-responsive and HIF1α-regulated AAA+ ATPase ATAD2 shows high oncogenic potential in stomach cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5680.