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

Int J Mol Sci. 2022 Jul 27;23(15):8282. doi: 10.3390/ijms23158282.


Sirtuin 3 (SIRT3) deacetylase is a key regulator for chemoresistance in acute myeloid leukemia (AML) cells due to its capability of modulating mitochondrial metabolism and reactive oxygen species (ROS). SIRT3 is de-SUMOylated by SUMO-specific peptidase 1 (SENP1), which enhances its deacetylase activity. Therefore, dysregulation of SIRT3 SUMOylation may lead to fortified chemoresistance in AML. Indeed, SIRT3 de-SUMOylation was induced by chemotherapeutic agents, which in turn, exacerbated resistance against chemotherapies in AML by activating SIRT3 via preventing its proteasome degradation. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation including inhibition of transcription factor Hes Family BHLH Transcription Factor 1 (HES1), a downstream substrate of Notch1 signaling pathway, leading to increased fatty acids oxidation (FAO). Moreover, the SENP1 inhibitor momordin-Ic or HES1 overexpression synergized with cytarabine to eradicate AML cells in vitro and in xenograft mouse models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in the regulation of chemoresistance in AML via HES1-dependent FAO and provided a rationale for SIRT3 SUMOylation and FAO targeted interventions to improve chemotherapies in AML.

Keywords: AML chemoresistance; HES1; SIRT3 SUMOylation; fatty acid oxidation.

MeSH terms

  • Animals
  • Drug Resistance, Neoplasm / genetics
  • Fatty Acids / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Mice
  • Sirtuin 3* / genetics
  • Sirtuin 3* / metabolism
  • Sumoylation
  • Transcription Factor HES-1 / genetics
  • Transcription Factor HES-1 / metabolism


  • Fatty Acids
  • Hes1 protein, mouse
  • Sirt3 protein, mouse
  • Transcription Factor HES-1
  • HES1 protein, human
  • SIRT3 protein, human
  • Sirtuin 3