title: Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth.
abstract: Although the oxidative pentose phosphate pathway is important for tumor growth, how 6-phosphogluconate dehydrogenase (6PGD) in this pathway is upregulated in human cancers is unknown. We found that 6PGD is commonly activated in EGF-stimulated cells and human cancer cells by lysine acetylation. Acetylation at K76 and K294 of 6PGD promotes NADP(+) binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we identified DLAT and ACAT2 as upstream acetyltransferases of K76 and K294, respectively, and HDAC4 as the deacetylase of both sites. Expressing acetyl-deficient mutants of 6PGD in cancer cells significantly attenuated cell proliferation and tumor growth. This is due in part to reduced levels of 6PGD products ribulose-5-phosphate and NADPH, which led to reduced RNA and lipid biosynthesis as well as elevated ROS. Furthermore, 6PGD activity is upregulated with increased lysine acetylation in primary leukemia cells from human patients, providing mechanistic insights into 6PGD upregulation in cancer cells.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Changliang
authors.initials: C
authors.lastname: Shan
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Elf
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Quanjiang
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Hee-Bum
authors.initials: HB
authors.lastname: Kang
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Taro
authors.initials: T
authors.lastname: Hitosugi
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ruiting
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Xie
authors.affiliation: Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Tucker
authors.affiliation: Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
authors.forename: Ting-Lei
authors.initials: TL
authors.lastname: Gu
authors.affiliation: UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sudderth
authors.affiliation: UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: Shaoxiong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Radiology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Yuancheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Radiology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.affiliation: College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Peng R
authors.initials: PR
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Georgia Zhuo
authors.initials: GZ
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Arellano
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
authors.forename: Sumin
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA. Electronic address: jfan3@emory.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA. Electronic address: jchen@emory.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D009249:NADP / Q000378:metabolism; D009374:Neoplasms, Experimental; D010734:Phosphogluconate Dehydrogenase / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D055503:Protein Multimerization
chemical_list: D009249:NADP; D010734:Phosphogluconate Dehydrogenase; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D000101:Acetyl-CoA C-Acetyltransferase; D006655:Histone Deacetylases; D008239:Lysine