title: SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation.
abstract: Like most other types of cancer cells, leukaemia cells undergo metabolic reprogramming to support rapid proliferation through enhancing biosynthetic processes. Pentose phosphate pathway (PPP) plays a pivotal role in meeting the anabolic demands for cancer cells. However, the molecular mechanism by which PPP contributes to leukaemia remains elusive. Here, we report that leukaemia cell proliferation is dependent on the oxidative branch of PPP, in particular the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of G6PD reduces NADPH level in acute myeloid leukaemia (AML) cell lines. Exogenous lipid supplements partially restore the proliferation of G6PD-depleted cells. Deacetylase SIRT2 promotes NADPH production through deacetylating G6PD at lysine 403 (K403). Activation of G6PD by SIRT2 supports the proliferation and clonogenic activity of leukaemia cells. Chemical inhibitors against SIRT2 suppress G6PD activity, leading to reduced cell proliferation of leukaemia cells, but not normal hematopoietic stem and progenitor cells. Importantly, SIRT2 is overexpressed in clinical AML samples, while K403 acetylation is downregulated and G6PD catalytic activity is increased comparing to that of normal control. Together, our study reveals that acetylation regulation of G6PD is involved in the metabolic reprogramming of AML, and SIRT2 serves as a promising target for further therapeutic investigations.
authors: Department of Haematology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Shuang-Nian
authors: SN
authors: Xu
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumour Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 Chongqing South Rd., Shanghai 200025, China.
authors: Tian-Shi
authors: TS
authors: Wang
authors: Department of Haematology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Xi
authors: X
authors: Li
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumour Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 Chongqing South Rd., Shanghai 200025, China.
authors: Yi-Ping
authors: YP
authors: Wang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D009249:NADP / Q000032:analysis*; D056565:Sirtuin 2 / Q000378:metabolism*
chemical_list: D009249:NADP; D005954:Glucosephosphate Dehydrogenase; C474199:SIRT2 protein, human; D056565:Sirtuin 2