ATP-citrate lyase: carcinogenesis and therapeutic advances

Abstract

ATP citrate lyase (ACLY) is involved in acetyl-coenzyme A synthesis and protein acetylation, thereby increasing lipid metabolism and altering protein metabolism to affect cellular metabolism. Additionally, ACLY is associated with various biological and pathological functions, especially regarding tumorigenesis. It facilitates the progression of various cancer types, including liver, lung, breast, prostate, and colorectal cancers. Mechanisms underlying ACLY-mediated carcinogenesis are under investigation and may not be limited to energy metabolism and biosynthesis. Acetylation modification of specific signaling molecules and transcription factors is considered a potential mechanism of ACLY-mediated tumorigenesis and offers novel insights and potential targets for the clinical treatment of tumors. Furthermore, the antitumor effect of pharmacological ACLY-inhibiting agents, including various small molecules or naturally active compounds, has been reported, albeit their practical application in clinical settings remains limited. This study aims to comprehensively review the oncogenic role of ACLY, with a focus on major collaborators and regulatory genes.

1. Introduction

ATP citrate lyase (ACLY) is a key enzyme that catalyzes the conversion of citrate to acetyl-coenzyme A (CoA). Mitochondria-produced acetyl-CoA is not able to shuttle freely through the inner membrane of mitochondria, and its entry into the cytoplasm relies on citrate in the Krebs cycle as an acetyl carrier, which is then catalyzed by ACLY to regenerate acetyl-CoA and oxaloacetate (OAA) in the cytoplasm (Figure 1A) [1]. ACLY plays a critical role in energy/lipid metabolism, acetylation modification of histone/non-histone proteins, and immune response, involving cancer cell initiation, progression, and immune escape. The ACLY gene encodes a homotetramer protein consisting of four identical subunits, each of which is divided into six structural domains; it can be roughly divided into an N-terminal acyl-CoA synthetase homology (ASH) superdomain and a C-terminal citrate synthase homology (CSH) domain [2,3]. The CSH domain is a rigid domain, flanked by four flexible ASH domains, which bind to both the substrate (citrate) and products (acetyl-CoA and OAA) (Figure 1B) [4,5]. Moreover, the N-terminal domain participates in the allosteric regulation of the enzyme and can alter ACLY’s conformation to modulate its enzymatic activity, following binding with effector molecules. In contrast, the C-terminal domain is primarily involved in stabilizing the enzyme structure. It exhibits different interactions compared with those of the N-terminal domain and can bind with auxiliary factors to affect enzymatic catalysis. Moreover, it may guide the enzyme to specific organelles or cellular regions for targeted localization in certain cases [2,3].

ACLY is involved in various physiological processes, such as metabolism regulation at the cellular level. ACLY converts substrates (citrate and CoA) to acetyl-CoA and OAA, which are involved in glycolysis and gluconeogenesis, respectively; and ACLY-catalyzed reaction product acetyl-CoA can be carboxylated to malonyl-CoA, which determines the rate of the first step in fatty acid synthesis [6]. Additionally, acetyl-CoA participates in the mevalonate pathway to produce acetoacetyl-CoA, which is further converted to cholesterol. Therefore, the ACLY gene has been found to be a key cancer gene in human cancer owing to its effects on lipid and cholesterol synthesis [7,8], and targeting ACLY can reverse aberrant lipid signaling pathways, which benefits cancer treatment and recovery [9,10]. In addition to metabolic pathways, the tumorigenic effects of ACLY also involve epigenetic regulation (e.g., acetylation modification of histones), post-translational modification of proteins (e.g., acetylation modification of non-histone proteins), transcriptional regulation, and tumor immunity. In particular, the emergence of small molecule inhibitors targeting ACLY has provided novel avenues for the treatment of ACLY-driven metabolic diseases or tumors, although most have not yet entered clinical care. In brief, growing bodies of research have provided novel insights into the role of ACLY in cancer progression; our review comprehensively summarizes the oncogenic role of ACLY, primarily focusing on its critical role in cancer progression and associated tissue-specific influencing factors.