Caspase-10 Inhibits ATP-citrate Lyase-mediated Metabolic and Epigenetic Reprogramming to Suppress Tumorigenesis

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Sep 20

PMID 31534141

Citations 24

Authors

Rajni Kumari

Ruhi S Deshmukh

Sanjeev Das

Affiliations

Soon will be listed here.

Abstract

Caspase-10 belongs to the class of initiator caspases and is a close homolog of caspase-8. However, the lack of caspase-10 in mice and limited substrate repertoire restricts the understanding of its physiological functions. Here, we report that ATP-citrate lyase (ACLY) is a caspase-10 substrate. Caspase-10 cleaves ACLY at the conserved Asp1026 site under conditions of altered metabolic homeostasis. Cleavage of ACLY abrogates its enzymatic activity and suppresses the generation of acetyl-CoA, which is critical for lipogenesis and histone acetylation. Thus, caspase-10-mediated ACLY cleavage results in reduced intracellular lipid levels and represses GCN5-mediated histone H3 and H4 acetylation. Furthermore, decline in GCN5 activity alters the epigenetic profile, resulting in downregulation of proliferative and metastatic genes. Thus caspase-10 suppresses ACLY-promoted malignant phenotype. These findings expand the substrate repertoire of caspase-10 and highlight its pivotal role in inhibiting tumorigenesis through metabolic and epigenetic mechanisms.

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References

Li J, Chen P, Sinogeeva N, Gorospe M, Wersto R, Chrest F . Arsenic trioxide promotes histone H3 phosphoacetylation at the chromatin of CASPASE-10 in acute promyelocytic leukemia cells. J Biol Chem. 2002; 277(51):49504-10. DOI: 10.1074/jbc.M207836200. View

Hatzivassiliou G, Zhao F, Bauer D, Andreadis C, Shaw A, Dhanak D . ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005; 8(4):311-21. DOI: 10.1016/j.ccr.2005.09.008. View

Fernandes-Alnemri T, Armstrong R, Krebs J, Srinivasula S, Wang L, Bullrich F . In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc Natl Acad Sci U S A. 1996; 93(15):7464-9. PMC: 38767. DOI: 10.1073/pnas.93.15.7464. View

SRERE P . The citrate cleavage enzyme. I. Distribution and purification. J Biol Chem. 1959; 234:2544-7. View

Park W, Lee J, Shin M, Park J, Kim H, Lee J . Inactivating mutations of the caspase-10 gene in gastric cancer. Oncogene. 2002; 21(18):2919-25. DOI: 10.1038/sj.onc.1205394. View

Wellen K, Hatzivassiliou G, Sachdeva U, Bui T, Cross J, Thompson C . ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009; 324(5930):1076-80. PMC: 2746744. DOI: 10.1126/science.1164097. View

Veluthakal R, Arora D, Goalstone M, Kowluru R, Kowluru A . Metabolic Stress Induces Caspase-3 Mediated Degradation and Inactivation of Farnesyl and Geranylgeranyl Transferase Activities in Pancreatic β-Cells. Cell Physiol Biochem. 2016; 39(6):2110-2120. PMC: 6685439. DOI: 10.1159/000447907. View

Shao W, Yeretssian G, Doiron K, Hussain S, Saleh M . The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock. J Biol Chem. 2007; 282(50):36321-9. DOI: 10.1074/jbc.M708182200. View

Zhang C, Liu J, Huang G, Zhao Y, Yue X, Wu H . Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev. 2016; 30(17):1956-70. PMC: 5066239. DOI: 10.1101/gad.283283.116. View

10.

Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M . ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 2008; 68(20):8547-54. DOI: 10.1158/0008-5472.CAN-08-1235. View

11.

Pinkosky S, Newton R, Day E, Ford R, Lhotak S, Austin R . Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016; 7:13457. PMC: 5133702. DOI: 10.1038/ncomms13457. View

12.

Morgan M, Thorburn J, Thomas L, Maxwell T, Brothman A, Thorburn A . An apoptosis signaling pathway induced by the death domain of FADD selectively kills normal but not cancerous prostate epithelial cells. Cell Death Differ. 2001; 8(7):696-705. DOI: 10.1038/sj.cdd.4400866. View

13.

Rosebeck S, Alonge M, Kandarpa M, Mayampurath A, Volchenboum S, Jasielec J . Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10-Dependent Apoptosis by Carfilzomib and Selinexor. Mol Cancer Ther. 2015; 15(1):60-71. DOI: 10.1158/1535-7163.MCT-15-0488. View

14.

Sun T, Hayakawa K, Bateman K, Fraser M . Identification of the citrate-binding site of human ATP-citrate lyase using X-ray crystallography. J Biol Chem. 2010; 285(35):27418-27428. PMC: 2930740. DOI: 10.1074/jbc.M109.078667. View

15.

Milhas D, Cuvillier O, Therville N, Clave P, Thomsen M, Levade T . Caspase-10 triggers Bid cleavage and caspase cascade activation in FasL-induced apoptosis. J Biol Chem. 2005; 280(20):19836-42. DOI: 10.1074/jbc.M414358200. View

16.

Sato R, Okamoto A, Inoue J, Miyamoto W, Sakai Y, Emoto N . Transcriptional regulation of the ATP citrate-lyase gene by sterol regulatory element-binding proteins. J Biol Chem. 2000; 275(17):12497-502. DOI: 10.1074/jbc.275.17.12497. View

17.

Boatright K, Deis C, Denault J, Sutherlin D, Salvesen G . Activation of caspases-8 and -10 by FLIP(L). Biochem J. 2004; 382(Pt 2):651-7. PMC: 1133822. DOI: 10.1042/BJ20040809. View

18.

Lamy L, Ngo V, Emre N, Shaffer 3rd A, Yang Y, Tian E . Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell. 2013; 23(4):435-49. PMC: 4059832. DOI: 10.1016/j.ccr.2013.02.017. View

19.

Wachmann K, Pop C, van Raam B, Drag M, Mace P, Snipas S . Activation and specificity of human caspase-10. Biochemistry. 2010; 49(38):8307-15. PMC: 2943529. DOI: 10.1021/bi100968m. View

20.

Schug Z, Peck B, Jones D, Zhang Q, Grosskurth S, Alam I . Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. 2015; 27(1):57-71. PMC: 4297291. DOI: 10.1016/j.ccell.2014.12.002. View