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

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 α(2)-Macroglobulin (α(2)M(*)) signals through tumor Cell Surface GRP78 (CS-GRP78) to regulate tumor cell proliferation through multiple signaling pathway. Here, we demonstrate that the α(2)M(*)/CS-GRP78 axis regulates acetyl-CoA synthesis and thus functions as an epigenetic modulator by enhancing histone acetylation in cancer cells. α(2)M(*)/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 α(2)M(*)/CS-GRP78 signaling is a central mechanism for integrating glucose and acetate-dependent signaling to induce histone acetylation. More importantly, targeting the α(2)M(*)/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 α(2)M(*)/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.