Advances into understanding metabolites as signaling molecules in cancer progression

Abstract

Recent years have seen a great expansion in our knowledge of the roles that metabolites play in cellular signaling. Structural data have provided crucial insights into mechanisms through which amino acids are sensed. New nutrient-coupled protein and RNA modifications have been identified and characterized. A growing list of functions has been ascribed to metabolic regulation of modifications such as acetylation, methylation, and glycosylation. A current challenge lies in developing an integrated understanding of the roles that metabolic signaling mechanisms play in physiology and disease, which will inform the design of strategies to target such mechanisms. In this brief article, we review recent advances in metabolic signaling through post-translational modification during cancer progression, to provide a framework for understanding signaling roles of metabolites in the context of cancer biology and illuminate areas for future investigation.

Keywords: Cancer; Metabolic signaling; Metabolism.

Figure 1.. Metabolites regulate TET methylcytosine oxidases to impact tumor formation

Metabolically-linked alterations in TET activity have been identified as consequences of both oncogene activation and tumor suppressor silencing. TET enzymes, which belong to the family of 2-oxoglutarate-dependent dioxygenases that rely on αKG as a cosubstrate, mediate the oxidation of 5-methylcytosine (5mC) to yield 5-hydroxymethylcytosine (5hmC) and subsequently 5-fC and 5-caC, to facilitate removal of DNA methylation. Oncogenic mutations in isocitrate dehydrogenase (IDH) lead to neomorphic activity and production of the oncometabolite D-2-hydroxyglutarate (D-2-HG). The stereoisomer L-2-HG can also be generated under hypoxia or accumulate upon loss of L-2-HG dehydrogenase activity. Succinate dehydrogenase (SDH) and fumarate hydratase (FH) loss of function drive accumulation of succinate and fumarate, respectively. 2-HG, succinate, and fumarate all inhibit the activity of TET enzymes. Conversely, increasing the αKG: succinate ratio, which has been identified as a component of the p53 tumor suppressive program[15], is associated with promotion of TET activity.

Figure 2.. Acetyl-CoA mediates signaling functions throughout cancer progression

The signaling functions of metabolites have been implicated in multiple steps throughout tumorigenesis, including tumor initiation, metastasis, and in interaction with other cell types (immune, cancer-associated stroma). Here, acetyl-CoA is shown as a representative example. Nuclear-cytosolic acetyl-CoA is generated from mitochondria-derived citrate via ATP-citrate lyase (ACLY) or acetate via acyl-CoA synthetase short-chain family member 2 (ACSS2). This pool of acetyl-CoA feeds into multiple biosynthetic pathways and also serves as the sole substrate for acetylation reactions, mediated by lysine acetyl-transferases (KATs). ACLY-dependent elevations in acetyl-CoA and global histone acetylation were observed in KRAS mutant pancreatic acinar cells[23]. Accumulations in acetyl-CoA are also implicated in regulation of metastasis. In two models of cancer, inhibition of acetyl-CoA consuming enzymes acyl-CoA thioester 12 (ACOT12) and acetyl-CoA carboxylase (ACC) increased the expression or activity of EMT transcription factors Twist2 and Smad2 via histone or transcription factor acetylation, respectively[33,34]. Lastly, control of acetyl-CoA production in T cells, partly under the control of the transcription factor Bhlhe40, and histone acetylation are implicated in regulating IFNγ production and antitumor immunity[54,55,81].

Figure 3.. Nutrient availability and αKG regulate aspects of metastatic biology in breast Cancer

In metastatic breast cancer cells, αKG metabolism participates in extracellular matrix remodeling (ECM), stemness and chemoresistance. Pyruvate uptake promotes production of αKG through alanine aminotransferase (ALT). αKG is required by collagen prolyl-4-hydroxylase (P4HA) to hydroxylate procollagen for stable collagen synthesis in the process of ECM remodeling[39]. This shunting of αKG toward P4HA1 also limits HIF hydroxylation, resulting in stabilization and transcription of genes involved in chemoresistance and stemness[42].

Figure 4.. Novel mechanisms toward the production of nuclear acetyl-CoA

ACLY, ACSS2, and PDC have all been found within the nucleus for local and context-specific generation of acetyl-CoA. Breakdown of nuclear glycogen into pyruvate has been identified as a novel source of acetyl-CoA for histone acetylation [71]. Nuclear-generated pyruvate could in principle contribute to histone acetylation through PDC-dependent production of acetyl-CoA [72] or through non-enzymatic conversion of pyruvate to acetate and subsequent acetyl-CoA generation by ACSS2[73]. Nuclear transport and deacetylation of newly synthesized H4 histones has also been proposed as a source of acetate for acetylation of histones at promoters of histone H4 genes [70].