Elevated 2-oxoglutarate antagonizes DNA damage responses in cholangiocarcinoma chemotherapy through regulating aspartate beta-hydroxylase

• Published in: Cancer letters 2024-01, Vol.580, p.216493-216493, Article 216493
• Main Authors: Nagaoka, Katsuya, Bai, Xuewei, Liu, Dan, Cao, Kevin, Mulla, Joud, Ji, Chengcheng, Chen, Hongze, Nisar, Muhammad Azhar, Bay, Amalia, Mueller, William, Hildebrand, Grace, Gao, Jin-Song, Lu, Shaolei, Setoyama, Hiroko, Tanaka, Yasuhito, Wands, Jack R., Huang, Chiung-Kuei
• Format: Article
• Language: English
• Subjects: Aspartic Acid - metabolism; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - genetics; Bile Ducts, Intrahepatic; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - genetics; DNA Damage; Humans; Ketoglutaric Acids; Mixed Function Oxygenases - genetics
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2023.216493

Cholangiocarcinoma (CCA) is resistant to systemic chemotherapies that kill malignant cells mainly through DNA damage responses (DDRs). Recent studies suggest that the involvement of 2-oxoglutarate (2-OG) dependent dioxygenases in DDRs may be associated with chemoresistance in malignancy, but how 2-OG impacts DDRs in CCA chemotherapy remains elusive. We examined serum 2-OG levels in CCA patients before receiving chemotherapy. CCA patients are classified as progressive disease (PD), partial response (PR), and stable disease (SD) after receiving chemotherapy. CCA patients classified as PD showed significantly higher serum 2-OG levels than those defined as SD and PR. Treating CCA cells with 2-OG reduced DDRs. Overexpression of full-length aspartate beta-hydroxylase (ASPH) could mimic the effects of 2-OG on DDRs, suggesting the important role of ASPH in chemoresistance. Indeed, the knockdown of ASPH improved chemotherapy in CCA cells. Targeting ASPH with a specific small molecule inhibitor also enhanced the effects of chemotherapy. Mechanistically, ASPH modulates DDRs by affecting ATM and ATR, two of the major regulators finely controlling DDRs. More importantly, targeting ASPH improved the therapeutic potential of chemotherapy in two preclinical CCA models. Our data suggested the impacts of elevated 2-OG and ASPH on chemoresistance through antagonizing DDRs. Targeting ASPH may enhance DDRs, improving chemotherapy in CCA patients. •Elevated 2-oxoglutarate levels in cholangiocarcinoma patients predict poor prognosis in chemotherapy.•2-oxoglutarate treatment antagonizes DNA damage responses in cholangiocarcinoma through aspartate beta-hydroxylase.•The ATM and ATR kinase functions are required in the aspartate beta-hydroxylase mediated DNA damage responses.•Targeting aspartate beta-hydroxylase improves the therapeutic effects of chemotherapy.