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

Abstract

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.

Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism

“…Taken together, our observations indicate that the RP, Rpl22, employs a novel mode of action to regulate the transformation potential of HSC that does not involve altering global protein synthesis, but is instead focused on the control of cellular lipid metabolism, by regulating the expression of the lipoxygenase, Alox12. Importantly, perturbations in lipid metabolism are increasingly understood to represent therapeutic vulnerabilities in AML (Buettner et al, 2021;Hoang et al, 2022;Jones et al, 2020;Ling et al, 2023;O'Brien et al, 2023;Stevens et al, 2020;Zhang et al, 2022); however, past efforts to pharmacologically attenuate FAO in patients have been limited by liver toxicity (Holubarsch et al, 2007;Jin et al, 2008). Our findings suggest that targeting the lipoxygenases that regulate FAO may represent another fruitful approach, particularly in those patients with RPL22-insufficiency.…”

Sirtuins at the Crossroads between Mitochondrial Quality Control and Neurodegenerative Diseases: Structure, Regulation, Modifications, and Modulators

“…SUMOylation negatively regulated SIRT3 enzymatic activity. SENP1-mediated SIRT3 de-SUMOylation at lysine 288 upregulated its deacetylase activity and participated in mitochondrial metabolism [ 163 ]. SIRT3 can also be modified by acetylation.…”

Emerging role of SENP1 in tumorigenesis and cancer therapy

“…The deSUMOylation of HK2 mediated by SENP1 desensitizes chemotherapy response in prostate cancer cells with docetaxel treatment ( Shangguan et al, 2021 ). SENP1 activates sirtuin 3 (SIRT3) by preventing its proteasome degradation through which exacerbates resistance against chemotherapy in acute myeloid leukemia (AML) cells ( Zhang et al, 2022 ). In MM cells, SENP1 is regarded as a key modifier of steroid receptor coactivator-3 (SRC-3) stability.…”