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Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation

Yirong Zhang1, Yajie Shen1,2, Weiqing Wei1

  • 1Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

International Journal of Molecular Sciences
|August 12, 2022
PubMed

Insights

Sirtuin 3 (SIRT3) SUMOylation regulates chemoresistance in acute myeloid leukemia (AML). Inhibiting SENP1 or overexpressing HES1 enhances chemotherapy efficacy by targeting fatty acid oxidation (FAO) in AML cells.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • Sirtuin 3 (SIRT3) deacetylase activity influences chemoresistance in acute myeloid leukemia (AML) by regulating mitochondrial metabolism and reactive oxygen species (ROS).
  • SUMO-specific peptidase 1 (SENP1) enhances SIRT3 deacetylase activity through de-SUMOylation.
  • Dysregulation of SIRT3 SUMOylation is implicated in AML chemoresistance.

Purpose of the Study:

  • To investigate the role of SIRT3 SUMOylation in regulating chemoresistance in acute myeloid leukemia (AML).
  • To explore the underlying mechanisms involving fatty acid oxidation (FAO) and the Notch1 signaling pathway.
  • To evaluate potential therapeutic strategies targeting SIRT3 SUMOylation and FAO in AML.

Main Methods:

  • RNA sequencing (RNA-seq) to analyze gene expression changes.
  • In vitro and in vivo experiments using AML cell lines and xenograft mouse models.
  • Assessment of SIRT3 de-SUMOylation, HES1 expression, and FAO levels.
  • Evaluation of drug synergy with cytarabine.

Main Results:

  • Chemotherapeutic agents induced SIRT3 de-SUMOylation, increasing AML chemoresistance by preventing proteasome degradation.
  • SIRT3 de-SUMOylation altered gene expression, inhibiting Hes Family BHLH Transcription Factor 1 (HES1) and increasing fatty acid oxidation (FAO).
  • SENP1 inhibition (momordin-Ic) or HES1 overexpression synergized with cytarabine to eradicate AML cells.

Conclusions:

  • SIRT3 SUMOylation plays a novel role in regulating AML chemoresistance through HES1-dependent FAO.
  • Targeting SIRT3 SUMOylation and FAO presents a promising therapeutic strategy to enhance AML chemotherapy.
Keywords:
AML chemoresistanceHES1SIRT3 SUMOylationfatty acid oxidation

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