1. SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis.
- Author
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Yu PC, Hou D, Chang B, Liu N, Xu CH, Chen X, Hu CL, Liu T, Wang X, Zhang Q, Liu P, Jiang Y, Fei MY, Zong LJ, Zhang JY, Liu H, Chen BY, Chen SB, Wang Y, Li ZJ, Li X, Deng CH, Ren YY, Zhao M, Jiang S, Wang R, Jin J, Yang S, Xue K, Shi J, Chang CK, Shen S, Wang Z, He PC, Chen Z, Chen SJ, Sun XJ, and Wang L
- Subjects
- Humans, Animals, Mice, Chromatin metabolism, Aldehyde Reductase metabolism, Aldehyde Reductase genetics, Leukemia metabolism, Leukemia pathology, Leukemia genetics, Chromosomal Proteins, Non-Histone metabolism, Chromosomal Proteins, Non-Histone genetics, Chromatin Assembly and Disassembly, Carcinogenesis metabolism, Carcinogenesis pathology, Carcinogenesis genetics, Cell Line, Tumor, Transcription Factors metabolism, Transcription Factors genetics, Adenosine Triphosphatases, Fructose metabolism
- Abstract
A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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