SUCLG1 deficiency-induced histone succinylation impairs oncogene expression in acute myeloid leukemia

Mengqing Gao; Minhui Shi; Hao Ding; Lei Xu; Na Zhao; Li Wang; Shujuan Huang; Hui Jiang; Ekaterina Bourova-Flin; Jianqing Mi; Saadi Khochbin; Domenico Iuso; Xiaoyu Zhu

doi:10.1016/j.celrep.2025.116147

SUCLG1 deficiency-induced histone succinylation impairs oncogene expression in acute myeloid leukemia

Cell Rep. 2025 Aug 26;44(8):116147. doi: 10.1016/j.celrep.2025.116147. Epub 2025 Aug 12.

Authors

Mengqing Gao¹, Minhui Shi², Hao Ding³, Lei Xu⁴, Na Zhao¹, Li Wang⁵, Shujuan Huang⁵, Hui Jiang⁵, Ekaterina Bourova-Flin⁶, Jianqing Mi⁷, Saadi Khochbin⁶, Domenico Iuso⁸, Xiaoyu Zhu⁹

Affiliations

¹ Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230027, China.
² Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230027, China; Section of Experimental Hematology, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
³ Department of Statistics and Finance, School of Management, University of Science and Technology of China, Hefei 230026, China.
⁴ Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
⁵ Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
⁶ Univ. Grenoble-Alpes, CNRS UMR 5309, INSERM U1209, Institute for Advanced Biosciences, 38706 La Tronche, France.
⁷ Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁸ Department of Veterinary Medicine, University of Teramo, 64100 Teramo, Italy. Electronic address: diuso@unite.it.
⁹ Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230027, China. Electronic address: xiaoyuz@ustc.edu.cn.

PMID: 40811057
DOI: 10.1016/j.celrep.2025.116147

Abstract

Mitochondria-driven histone lysine succinylation is emerging as a critical signaling system that links cellular metabolism to the pathogenesis of diseases, including cancer. Here, we report that a global increase in protein/histone succinylation is associated with mitochondrial tricarboxylic acid cycle defects in acute myeloid leukemia (AML). Depletion of the succinyl-coenzyme A (CoA) synthetase alpha subunit SUCLG1 causes protein/histone hypersuccinylation in leukemia cells, which impairs cell proliferation and leukemia progression in xenograft models. Mechanistically, increased histone succinylation, which could compete with acetylation, attenuates the interaction of the bromodomain-containing protein 4 (BRD4) bromodomain with chromatin, hence disrupting BRD4-mediated leukemogenic gene transcription and restoring BRD4-dependent fine-tuned gene regulatory circuits. Our study uncovers the crucial role of metabolism-controlled histone succinylation in cancer development and highlights it as an innovative therapeutic approach.

Keywords: BRD4; CP: Cancer; CP: Metabolism; SUCLG1; acute myeloid leukemia; histone succinylation.

MeSH terms

Acetylation
Animals
Bromodomain Containing Proteins
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Leukemic
Histones* / metabolism
Humans
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Leukemia, Myeloid, Acute* / pathology
Mice
Mitochondria / metabolism
Oncogenes* / genetics
Succinate-CoA Ligases* / deficiency
Succinate-CoA Ligases* / genetics
Succinate-CoA Ligases* / metabolism
Succinic Acid* / metabolism
Transcription Factors / metabolism

Substances

Histones
Transcription Factors
Succinate-CoA Ligases
Cell Cycle Proteins
BRD4 protein, human
Succinic Acid
Bromodomain Containing Proteins