Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation
Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct metabolic processes. Here, we identify succinate dehydrogenase (SDH) deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to various anti-cancer therapies. Mechanistically, succinate promotes the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function is mediated by succinate-triggered upregulation of ubiquitin-conjugating enzyme E2M (UBC12) phosphorylation, which impairs its E2 function in cullins neddylation. Notably, decreasing succinate by fludarabine can restore the sensitivity of anti-cancer drugs in SDH-deficient AML. Together, we uncover the function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.
Authors
- Senfeng Xiang
- Meidan Ying (ORCID: https://orcid.org/0000-0003-0039-9683)
- Xuejing Shao (ORCID: https://orcid.org/0000-0002-6907-0184)
- Miao Xian (ORCID: https://orcid.org/0009-0007-6001-1077)
- Ji Cao (ORCID: https://orcid.org/0000-0003-2813-6404)
- Xiaomin Wang (ORCID: https://orcid.org/0000-0002-0516-5061)
- Wenwen Ying
- Shaowei Bing
- Xiaojun Xu (ORCID: https://orcid.org/0000-0003-1388-2535)
- Yifan Chen (ORCID: https://orcid.org/0000-0002-7757-4462)
- Qiaojun He (ORCID: https://orcid.org/0000-0002-0104-6989)
- Jiayi Yu (ORCID: https://orcid.org/0000-0002-7663-0688)
- Bo Yang (ORCID: https://orcid.org/0000-0001-7356-0904)
- Jiayi Liu (ORCID: https://orcid.org/0000-0002-6010-9492)
Institutions
- Ministry of Education of the People's Republic of China (CN)
- Zhejiang Cancer Hospital (CN)
- Children's Hospital of Zhejiang University (CN)
- Anticancer Fund (BE)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1038/s41467-024-53398-9
- Citations
- 14
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 3.27
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Natural Science Foundation for Young Scientists of Shanxi Province
- Young Scientists Fund
- Natural Science Foundation of Zhejiang Province
- Science Fund for Distinguished Young Scholars of Zhejiang Province