Oncotarget

Research Papers:

Cell surface GRP78 promotes tumor cell histone acetylation through metabolic reprogramming: a mechanism which modulates the Warburg effect

Udhayakumar Gopal and Salvatore V. Pizzo _

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Oncotarget. 2017; 8:107947-107963. https://doi.org/10.18632/oncotarget.22431

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Abstract

Udhayakumar Gopal1,* and Salvatore V. Pizzo1,*

1Department of Pathology, Duke University Medical Center, Durham, NC, USA

*These authors have contributed equally to this work

Correspondence to:

Salvatore V. Pizzo, email: Salvatore.Pizzo@duke.edu

Keywords: Cell Surface GRP78; α2M*; histone acetylation; acetyl-CoA; metabolism

Received: April 05, 2017     Accepted: July 26, 2017     Published: November 14, 2017

ABSTRACT

Acetyl coenzyme A (acetyl-CoA) is essential for histone acetylation, to promote cell proliferation by regulating gene expression. However, the underlying mechanism(s) governing acetylation remains poorly understood. Activated α2-Macroglobulin (α2M*) signals through tumor Cell Surface GRP78 (CS-GRP78) to regulate tumor cell proliferation through multiple signaling pathway. Here, we demonstrate that the α2M*/CS-GRP78 axis regulates acetyl-CoA synthesis and thus functions as an epigenetic modulator by enhancing histone acetylation in cancer cells. α2M*/CS-GRP78 signaling induces and activates glucose-dependent ATP-citrate lyase (ACLY) and promotes acetate-dependent Acetyl-CoA Synthetase (ACSS1) expression by regulating AKT pathways to acetylate histones and other proteins. Further, we show that acetate itself regulates ACLY and ACSS1 expression through a feedback loop in an AKT-dependent manner. These studies demonstrate that α2M*/CS-GRP78 signaling is a central mechanism for integrating glucose and acetate-dependent signaling to induce histone acetylation. More importantly, targeting the α2M*/CS-GRP78 axis with C38 Monoclonal antibody (Mab) abrogates acetate-induced acetylation of histones and proteins essential for proliferation and survival under hypoxic stress. Furthermore, C38 Mab significantly reduced glucose uptake and lactate consumption which definitively suggests the role of aerobic glycolysis. Collectively, besides its ability to induce fatty acid synthesis, our study reveals a new mechanism of epigenetic regulation by the α2M*/CS-GRP78 axis to increase histone acetylation and promote cell survival under unfavorable condition. Therefore CS-GRP78 might be effectively employed to target the metabolic vulnerability of a wide spectrum of tumors and C38 Mab represents such a potential therapeutic agent.


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