O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation

Lorela Ciraku; Zachary A Bacigalupa; Jing Ju; Rebecca A Moeller; Giang Le Minh; Rusia H Lee; Michael D Smith; Christina M Ferrer; Sophie Trefely; Luke T Izzo; Mary T Doan; Wiktoria A Gocal; Luca D'Agostino; Wenyin Shi; Joshua G Jackson; Christos D Katsetos; Kathryn E Wellen; Nathaniel W Snyder; Mauricio J Reginato

doi:10.1038/s41388-022-02237-6

O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation

Lorela Ciraku, Zachary A Bacigalupa, Jing Ju, Rebecca A Moeller, Giang Le Minh, Rusia H Lee, Michael D Smith, Christina M Ferrer, Sophie Trefely, Luke T Izzo, Mary T Doan, Wiktoria A Gocal, Luca D'Agostino, Wenyin Shi, Joshua G Jackson, Christos D Katsetos, Kathryn E Wellen, Nathaniel W Snyder, Mauricio J Reginato

Cancer Signaling and Microenvironment (CSM)

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA and lipid production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA and lipids. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.

Original language	English
Pages (from-to)	2122-2136
Number of pages	15
Journal	Oncogene
Volume	41
Issue number	14
DOIs	https://doi.org/10.1038/s41388-022-02237-6
State	Published - Apr 1 2022

Keywords

Acetate-CoA Ligase/metabolism
Acetates/metabolism
Cell Line, Tumor
Glioblastoma
Humans
N-Acetylglucosaminyltransferases/metabolism
Phosphorylation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41388-022-02237-6

Cite this

Ciraku, L., Bacigalupa, Z. A., Ju, J., Moeller, R. A., Le Minh, G., Lee, R. H., Smith, M. D., Ferrer, C. M., Trefely, S., Izzo, L. T., Doan, M. T., Gocal, W. A., D'Agostino, L., Shi, W., Jackson, J. G., Katsetos, C. D., Wellen, K. E., Snyder, N. W., & Reginato, M. J. (2022). O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation. Oncogene, 41(14), 2122-2136. https://doi.org/10.1038/s41388-022-02237-6

@article{cb29afa2bcf6478eb386ca131f2e9228,

title = "O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation",

abstract = "Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA and lipid production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA and lipids. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.",

keywords = "Acetate-CoA Ligase/metabolism, Acetates/metabolism, Cell Line, Tumor, Glioblastoma, Humans, N-Acetylglucosaminyltransferases/metabolism, Phosphorylation",

author = "Lorela Ciraku and Bacigalupa, {Zachary A} and Jing Ju and Moeller, {Rebecca A} and {Le Minh}, Giang and Lee, {Rusia H} and Smith, {Michael D} and Ferrer, {Christina M} and Sophie Trefely and Izzo, {Luke T} and Doan, {Mary T} and Gocal, {Wiktoria A} and Luca D'Agostino and Wenyin Shi and Jackson, {Joshua G} and Katsetos, {Christos D} and Wellen, {Kathryn E} and Snyder, {Nathaniel W} and Reginato, {Mauricio J}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = apr,

day = "1",

doi = "10.1038/s41388-022-02237-6",

language = "English",

volume = "41",

pages = "2122--2136",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Nature Publishing Group",

number = "14",

}

Ciraku, L, Bacigalupa, ZA, Ju, J, Moeller, RA, Le Minh, G, Lee, RH, Smith, MD, Ferrer, CM, Trefely, S, Izzo, LT, Doan, MT, Gocal, WA, D'Agostino, L, Shi, W, Jackson, JG, Katsetos, CD, Wellen, KE, Snyder, NW & Reginato, MJ 2022, 'O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation', Oncogene, vol. 41, no. 14, pp. 2122-2136. https://doi.org/10.1038/s41388-022-02237-6

TY - JOUR

T1 - O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation

AU - Ciraku, Lorela

AU - Bacigalupa, Zachary A

AU - Ju, Jing

AU - Moeller, Rebecca A

AU - Le Minh, Giang

AU - Lee, Rusia H

AU - Smith, Michael D

AU - Ferrer, Christina M

AU - Trefely, Sophie

AU - Izzo, Luke T

AU - Doan, Mary T

AU - Gocal, Wiktoria A

AU - D'Agostino, Luca

AU - Shi, Wenyin

AU - Jackson, Joshua G

AU - Katsetos, Christos D

AU - Wellen, Kathryn E

AU - Snyder, Nathaniel W

AU - Reginato, Mauricio J

PY - 2022/4/1

Y1 - 2022/4/1

N2 - Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA and lipid production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA and lipids. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.

AB - Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA and lipid production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA and lipids. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.

KW - Acetate-CoA Ligase/metabolism

KW - Acetates/metabolism

KW - Cell Line, Tumor

KW - Glioblastoma

KW - Humans

KW - N-Acetylglucosaminyltransferases/metabolism

KW - Phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=85125228433&partnerID=8YFLogxK

U2 - 10.1038/s41388-022-02237-6

DO - 10.1038/s41388-022-02237-6

M3 - Article

C2 - 35190642

SN - 0950-9232

VL - 41

SP - 2122

EP - 2136

JO - Oncogene

JF - Oncogene

IS - 14

ER -

O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this