HIF1α-dependent upregulation of ATAD2 promotes proliferation and migration of stomach cancer cells in response to hypoxia

• Published in: Biochemical and biophysical research communications Vol. 523; no. 4; pp. 916 - 923
• Main Authors: Nayak, Aditi, Roy, Arjama Dhar, Rout, Niranjan, Singh, Shivaram Prasad, Bhattacharyya, Asima, Roychowdhury, Anasuya
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.03.2020
• Subjects: AAA+ ATPase; ATAD2; HIF1α; Hypoxia; Stomach or gastric cancer; SCCs; ATAD2; ChIP; AAA+ ATPase; Mut; Stomach or gastric cancer; ER-α; AAA + ATPase; HBS; Hypoxia; HAS; HIF1α; WT
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.12.130

Stomach cancer is a difficult-to-treat disease. Lack of detection markers and limited understanding of the disease mechanisms contribute to the aggressive nature of stomach cancer cells (SCCs). Recently, an ATPase, ATAD2 has been found to be highly expressed in stomach cancer contributing to increased malignancy. However, nothing is known about the mechanism of ATAD2 upregulation and its involvement in stomach carcinogenesis. Since hypoxic microenvironment plays a crucial role in the progression of solid tumors like stomach cancer; we have examined the regulation and function of ATAD2 expression in hypoxic SCCs. ATAD2 is induced in hypoxia-treated SCCs. Stomach adenocarcinoma and metastatic tissues with high HIF1α level also show enhanced ATAD2 expression. In the absence of hypoxia-inducible factor HIF1α, ATAD2 protein level is found to be less indicating towards a potential correlation between them. We identify the presence of HIF1α-binding site (HBS) and HIF1α ancillary site (HAS) in the ATAD2 promoter. Using both in vitro and in vivo binding studies, we confirm that HIF1α binds with the ATAD2 promoter in hypoxic condition. ATAD2 upregulation promotes proliferation and migration of SCCs exposed to hypoxia. Thus, we identify ATAD2 as a hypoxia-responsive and HIF1α-regulated gene and elucidate that upregulated expression of ATAD2 enhances tumor-promoting functions in hypoxic SCCs. Therefore, we propose ATAD2 as a promising therapeutic target for stomach cancer. [Display omitted] •ATAD2 expression is high in adenocarcinoma and metastatic stomach cancer tissues.•ATAD2 protein level is enhanced in hypoxic stomach cancer cells (SCCs).•HIF1α binds ATAD2 promoter at the HIF1α-binding site and transcribes ATAD2.•ATAD2 promotes proliferation and metastasis of SCCs exposed to hypoxia.