A role for ATP Citrate Lyase in cell cycle regulation during myeloid differentiation

Abstract

1Differentiation of myeloid progenitor cells into macrophages is accompanied by increased 2 PU.1 concentration and increasing cell cycle length, culminating in cell cycle arrest. Induction of 3 PU.1 expression in a cultured myeloid cell line expressing low PU.1 concentration results in 4 decreased levels of mRNA encoding ATP-Citrate Lyase (ACL) and cell cycle arrest. ACL is an 5 essential enzyme for generating acetyl-CoA, a key metabolite for the first step in fatty acid 6 synthesis as well as for histone acetylation. We hypothesized that ACL may play a role in cell 7 cycle regulation in the myeloid lineage. In this study, we found that acetyl-CoA or acetate 8 supplementation was sufficient to rescue cell cycle progression in cultured BN cells treated with 9 an ACL inhibitor or induced for PU.1 expression. Acetyl-CoA supplementation was also sufficient 10 to rescue cell cycle progression in BN cells treated with a fatty acid synthase (FASN) inhibitor. 11 We demonstrated that acetyl-CoA was utilized in both fatty acid synthesis and histone acetylation 12 pathways to promote proliferation. Finally, we found that Acly mRNA transcript levels decrease 13 during normal macrophage differentiation from bone marrow precursors. Our results suggest that 14 regulation of ACL activity is a potentially important point of control for cell cycle regulation in 15 the myeloid lineage. 16 Highly proliferating cells, including cancers, preferentially use glycolysis over oxidative 18 phosphorylation because, although it is less efficient at generating ATP, glycolysis is rapid and 19 provides key metabolites for several biosynthetic pathways including nucleotide, amino acid, and 20 fatty acid synthesis (1). This preferential use of glycolysis by cancer cells is known as the Warburg 21 effect (1, 2). Glycolysis results in the production of citrate that can be exported from mitochondria 22 to serve as the substrate for synthesis of acetyl-CoA by the enzyme ATP Citrate Lyase (ACL) (3). 23Acetyl-CoA is the required substrate of fatty acid synthase (FASN) in the first step of de novo fatty 24 acid synthesis. Although normal cells and cancer cells can utilize exogenous lipids, FASN-25 mediated fatty acid synthesis is required to sustain the needs of highly proliferative cells (4). Many 26 cancer types display increased endogenous fatty acid biosynthesis, regardless of the levels of 27 extracellular lipids available (5). Inhibiting FASN is effective in limiting the growth and 28 proliferation of cancer cells (4, 6). 29As a central metabolite, there are several anabolic and catabolic pathways that can lead to 30 the production of acetyl-CoA. These pathways can be located in mitochondria or in the cytoplasm 31 (7). Within the mitochondria, acetyl-CoA is generated in the matrix by the pyruvate dehydrogenase 32 complex, β-oxidation of fatty acids, and the catabolic metabolism of branched amino acids (7). In 33 the cytoplasm, ACL is the central enzyme for production of acetyl-CoA from citrate. Acetyl-CoA 34 synthetase 2 (ACSS2) can also gene...

Illuminating histidine phosphorylation in the pancreatic tumor microenvironment

“…FACS/immunoblot analyses revealed the presence of novel forms of G-3-pHis+ ACLY protein in TAMs (Fig 4). Although the role of ACLY in myeloid cells has been explored in the literature (Covarrubias et al, 2016; de Goede et al, 2021; Lauterbach et al, 2019; Namgaladze et al, 2018; Rhee et al, 2019; Verberk et al, 2021), the expression of non-canonical ACLY isoforms in CD11b+Ly6G-myeloid cells has not been previously described and the origin and function of these isoforms is the subject of ongoing research.…”

The E26 Transformation–Specific Family Transcription Factor Spi-C Is Dynamically Regulated by External Signals in B Cells

“…We selected Tp53 as a gene that is expected to be upregulated in unstimulated B cells because of its well-documented increase in expression during apoptosis (30). Acly was chosen as a gene expected to be downregulated because of its role in fatty acid synthesis during cell division (31). We found that Tp53 was upregulated over time by 12-fold in unstimulated B cells (Fig.…”

Meriolin1 induces cell cycle arrest, apoptosis, autophagy and targeting the Akt/MAPKs pathways in human neuroblastoma SH-SY5Y cells

“…The cell cycle is an irreversible process, and its progression is orchestrated through sequential activation of cyclin‐dependent kinases (CDKs) by their proper cyclin partner . In addition, CDK1/2/4/6 plays essential roles in cell cycle progression, which are highly disturbed in cancer cells . CDK4/6 mainly controls cell growth in G1 phase, CDK2 regulates chromosomal replication, and CDK1 regulates mitosis and meiosis .…”

“…[4] In addition, CDK1/2/4/6 plays essential roles in cell cycle progression, which are highly disturbed in cancer cells. [5,6] CDK4/6 mainly controls cell growth in G1 phase, CDK2 regulates chromosomal replication, and CDK1 regulates mitosis and meiosis. [4,5] Therefore, tumour cell growth is inhibited by arrest of the cell cycle.…”