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

Udhayakumar Gopal,Salvatore V Pizzo

doi:10.18632/oncotarget.22431

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.

Highlights

Metabolic reprogramming is an essential mechanism in cancer cell biology [1, 2]
To investigate the biological effect on cancer metabolism induced by α2M*/CS-Glucose Regulated Protein 78 (GRP78)-mediated histone acetylation we examined glucose consumption and lactate production in various cancer cell lines stimulated with α2M* and acetate alone or in combination in the absence and presence of AKT inhibitor GSK690693 (AKTi), ACLY inhibitor SB260089 (ACLYi), and C38 Monoclonal antibody (Mab)
In the present study we report that the α2M*/CS-GRP78 signaling axis regulates adenosine triphosphate (ATP)-citrate lyase (ACLY) and Acetyl-CoA Synthetase (ACSS1) expression by promoting AKT activation which ensures continuous acetyl-CoA production and global histone acetylation even during nutrient limitation

Summary

INTRODUCTION

Metabolic reprogramming is an essential mechanism in cancer cell biology [1, 2]. Acetyl-CoA, as a central metabolic intermediate, is widely used in macromolecule biosynthesis and energy production to support cancer cell proliferation. Recently we reported that the α2M*/CSGRP78 axis regulates metabolic alterations to enhance aerobic glycolysis and induce fatty acid synthesis in prostate cancer cells [36] It is not known whether the α2M*/CS-GRP78 axis contributes to histone acetylation by regulating metabolic reprogramming. These observations led us to hypothesis that the α2M*/ CS-GRP78 axis induces a metabolic adaptation through modulating acetyl-CoA production and histone acetylation in cancer cells. Consistent with this idea, we found that the α2M*/CS-GRP78 axis predominately activates expression of ACLY and ACSS1 through AKT signaling which in turn upregulates the acetyl-CoA production and histone acetylation. Beyond the role as a pro-proliferative signaling mechanism, our findings highlight an epigenetic role for the α2M*/CS-GRP78 axis in metabolic adaptation of cancer cells

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS