Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation.
Yirong ZhangYajie ShenWeiqing WeiWenhan WangDaiji JiangYizhuo RenZijing PengQiuju FanJinke ChengJiao MaPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- acute myeloid leukemia
- transcription factor
- oxidative stress
- ischemia reperfusion injury
- signaling pathway
- induced apoptosis
- fatty acid
- rna seq
- single cell
- allogeneic hematopoietic stem cell transplantation
- reactive oxygen species
- clinical trial
- physical activity
- hydrogen peroxide
- dna damage
- poor prognosis
- cell proliferation
- gene expression
- epithelial mesenchymal transition
- mouse model
- genome wide identification
- genome wide
- acute lymphoblastic leukemia
- dna methylation
- long non coding rna
- cancer therapy
- sensitive detection