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.
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References
Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012;26:756–84.
Schug ZT, Vande Voorde J, Gottlieb E. The metabolic fate of acetate in cancer. Nat Rev Cancer. 2016;16:708–17.
Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, et al. Acetate dependence of tumors. Cell. 2014;159:1591–602.
Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell. 2014;159:1603–14.
Lewis CA, Brault C, Peck B, Bensaad K, Griffiths B, Mitter R, et al. SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme. Oncogene. 2015;34:5128–40.
Yoshii Y, Furukawa T, Yoshii H, Mori T, Kiyono Y, Waki A, et al. Cytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism. Cancer Sci. 2009;100:821–7.
Zachara NE, Hart GW. O-GlcNAc modification: a nutritional sensor that modulates proteasome function. Trends Cell Biol. 2004;14:218–21.
Gao Y, Wells L, Comer FI, Parker GJ, Hart GW. Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic beta-N-acetylglucosaminidase from human brain. J Biol Chem. 2001;276:9838–45.
Bond MR, Hanover JA. A little sugar goes a long way: the cell biology of O-GlcNAc. J Cell Biol. 2015;208:869–80.
Ferrer CM, Sodi VL, Reginato MJ. O-GlcNAcylation in Cancer Biology: Linking Metabolism and Signaling. J Mol Biol. 2016;428:3282–94.
Caldwell SA, Jackson SR, Shahriari KS, Lynch TP, Sethi G, Walker S, et al. Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene. 2010;29:2831–42.
Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ. Critical role of O-Linked β-N-acetylglucosamine transferase in prostate cancer invasion, angiogenesis, and metastasis. J Biol Chem. 2012;287:11070–81.
Sodi VL, Bacigalupa ZA, Ferrer CM, Lee JV, Gocal WA, Mukhopadhyay D, et al. Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation. Oncogene. 2018;37:924–34.
Pozo K, Bibb JA. The emerging role of Cdk5 in cancer. Trends Cancer. 2016;2:606–18.
Antoniou X, Gassmann M, Ogunshola OO. Cdk5 interacts with Hif-1alpha in neurons: a new hypoxic signalling mechanism? Brain Res. 2011;1381:1–10.
Fu AK, Fu WY, Ng AK, Chien WW, Ng YP, Wang JH, et al. Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity. Proc Natl Acad Sci USA. 2004;101:6728–33.
Futatsugi A, Utreras E, Rudrabhatla P, Jaffe H, Pant HC, Kulkarni AB. Cyclin-dependent kinase 5 regulates E2F transcription factor through phosphorylation of Rb protein in neurons. Cell Cycle. 2012;11:1603–10.
Lindqvist J, Imanishi SY, Torvaldson E, Malinen M, Remes M, Orn F, et al. Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells. Mol Biol Cell. 2015;26:1971–84.
Sharma S, Zhang T, Michowski W, Rebecca VW, Xiao M, Ferretti R, et al. Targeting the cyclin-dependent kinase 5 in metastatic melanoma. Proc Natl Acad Sci USA. 2020;117:8001–12.
Lenjisa JL, Tadesse S, Khair NZ, Kumarasiri M, Yu M, Albrecht H, et al. CDK5 in oncology: recent advances and future prospects. Future Med Chem. 2017;9:1939–62.
Yushan R, Wenjie C, Suning H, Yiwu D, Tengfei Z, Madushi WM, et al. Insights into the clinical value of cyclin-dependent kinase 5 in glioma: a retrospective study. World J Surgical Oncol. 2015;13:223.
Catania A, Urban S, Yan E, Hao C, Barron G, Allalunis-Turner J. Expression and localization of cyclin-dependent kinase 5 in apoptotic human glioma cells. Neuro Oncol. 2001;3:89–98.
Liu R, Tian B, Gearing M, Hunter S, Ye K, Mao Z. Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion. Proc Natl Acad Sci USA. 2008;105:7570–5.
Gloster TM, Zandberg WF, Heinonen JE, Shen DL, Deng L, Vocadlo DJ. Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells. Nat Chem Biol. 2011;7:174–81.
Ferrer CM, Lynch TP, Sodi VL, Falcone JN, Schwab LP, Peacock DL, et al. O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol Cell. 2014;54:820–31.
Sodi VL, Khaku S, Krutilina R, Schwab LP, Vocadlo DJ, Seagroves TN, et al. mTOR/MYC Axis Regulates O-GlcNAc Transferase Expression and O-GlcNAcylation in Breast Cancer. Mol Cancer Res. 2015;13:923–33.
Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. 2015;27:57–71.
Kreppel LK, Blomberg MA, Hart GW. Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats. J Biol Chem. 1997;272:9308–15.
Obenauer JC, Cantley LC, Yaffe MB. Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs. Nucleic Acids Res. 2003;31:3635–41.
Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res 2015;43:D512–20.
Lin H, Chen MC, Chiu CY, Song YM, Lin SY. Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells. J Biol Chem. 2007;282:2776–84.
Piedrahita D, Hernandez I, Lopez-Tobon A, Fedorov D, Obara B, Manjunath BS, et al. Silencing of CDK5 reduces neurofibrillary tangles in transgenic alzheimer’s mice. J Neurosci. 2010;30:13966–76.
Parry D, Guzi T, Shanahan F, Davis N, Prabhavalkar D, Wiswell D, et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010;9:2344–53.
Jackson JG, O’Donnell JC, Takano H, Coulter DA, Robinson MB. Neuronal activity and glutamate uptake decrease mitochondrial mobility in astrocytes and position mitochondria near glutamate transporters. J Neurosci. 2014;34:1613–24.
Ning X, Tao T, Shen J, Ji Y, Xie L, Wang H, et al. The O-GlcNAc Modification of CDK5 Involved in Neuronal Apoptosis Following In Vitro Intracerebral Hemorrhage. Cell Mol Neurobiol. 2017;37:527–36.
Chau V, Tobias JW, Bachmair A, Marriott D, Ecker DJ, Gonda DK, et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science. 1989;243:1576–83.
Li X, Yu W, Qian X, Xia Y, Zheng Y, Lee JH, et al. Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy. Mol Cell. 2017;66:684–97 e9.
Parry D, Guzi T, Shanahan F, Davis N, Prabhavalkar D, Wiswell D, et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010;9:2344–53.
Magistretti PJ, Allaman I. A cellular perspective on brain energy metabolism and functional imaging. Neuron. 2015;86:883–901.
Schild T, Low V, Blenis J, Gomes AP. Unique metabolic adaptations dictate distal organ-specific metastatic colonization. Cancer Cell. 2018;33:347–54.
Ubeda M, Kemp DM, Habener JF. Glucose-induced expression of the cyclin-dependent protein kinase 5 activator p35 involved in Alzheimer’s disease regulates insulin gene transcription in pancreatic beta-cells. Endocrinology. 2004;145:3023–31.
Kumar SK, LaPlant B, Chng WJ, Zonder J, Callander N, Fonseca R, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125:443–8.
Feldmann G, Mishra A, Bisht S, Karikari C, Garrido-Laguna I, Rasheed Z, et al. Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol Ther. 2011;12:598–609.
Chen XX, Xie FF, Zhu XJ, Lin F, Pan SS, Gong LH, et al. Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer. Oncotarget. 2015;6:14926–39.
Bulusu V, Tumanov S, Michalopoulou E, van den Broek NJ, MacKay G, Nixon C, et al. Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation. Cell Rep. 2017;18:647–58.
Ferrer CM, Lynch TP, Sodi VL, Falcone JN, Schwab LP, Peacock DL, et al. O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol Cell. 2014;54:820–31.
Jin X, Demere Z, Nair K, Ali A, Ferraro GB, Natoli T, et al. A metastasis map of human cancer cell lines. Nature 2020;588:331–6.
Ferraro GB, Ali A, Luengo A, Kodack DP, Deik A, Abbott KL, et al. Fatty Acid Synthesis Is Required for Breast Cancer Brain Metastasis. Nat Cancer. 2021;2:414–28.
Hothi P, Martins TJ, Chen L, Deleyrolle L, Yoon JG, Reynolds B, et al. High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells. Oncotarget. 2012;3:1124–36.
Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19:649–58.
Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72.
Zhao S, Torres A, Henry RA, Trefely S, Wallace M, Lee JV, et al. ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch. Cell Rep. 2016;17:1037–52.
Trefely S, Ashwell P, Snyder NW. FluxFix: automatic isotopologue normalization for metabolic tracer analysis. BMC Bioinforma. 2016;17:485.
Ciraku L, Moeller RA, Esquea EM, Gocal WA, Hartsough EJ, Simone NL, et al. An Ex Vivo Brain Slice Model to Study and Target Breast Cancer Brain Metastatic Tumor Growth. J Vis Exp. 2021;175.
Thompson JW, Griffin ME, Hsieh-Wilson LC. Methods for the Detection, Study, and Dynamic Profiling of O-GlcNAc Glycosylation. Methods Enzymol. 2018;598:101–35.
Acknowledgements
This work was supported by PA CURE grant (to MJR, NWS and JGJ), UO1CA244303 (to MJR), Drexel University Dean’s Fellowship award (to ZAB and LC). KEW acknowledges R01CA228339. LTI is supported by 2-T32-CA-115299-14. The authors thank Chaitali Bhadiadra for technical assistance, Dr. Valerie Sodi and Dr. Edward Hartsough for helpful discussions. In memoriam Christos D. Katsetos.
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LC and ZAB performed most of the experimental work; GL, JJ, RAM, and RHL helped with experimental work; CMF helped establish intracranial mouse model; SF, MTD, LTI, KEW and NWS performed acetate labeling and analyzed data. WAG, LD and CDK helped with IHC and CDK performed pathological analysis; WS provided GBM tissue array; JGJ, LC, RAM helped establish ex vivo brain slice model. LC, ZAB and MJR participated in study conception and design as well as data analysis and interpretation; LC, ZAB and MJR drafted the manuscript; All co-authors reviewed the final manuscript version.
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Ciraku, L., Bacigalupa, Z.A., Ju, J. et al. O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation. Oncogene 41, 2122–2136 (2022). https://doi.org/10.1038/s41388-022-02237-6
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DOI: https://doi.org/10.1038/s41388-022-02237-6
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