Serine metabolism reprogramming in cancer: a multi-tiered regulatory framework

Abstract

As a critical component of amino acid metabolic reprogramming, serine metabolism has been demonstrated to be enhanced in a variety of cancer types, thereby supporting tumor progression. This enhancement is primarily driven by increased expression levels and augmented enzymatic activity of serine metabolic enzymes (phosphoglycerate dehydrogenase, phosphoserine aminotransferase 1, phosphoserine phosphatase and serine hydroxymethyltransferase). However, there is still lack of comprehensive summary on the regulation of serine metabolism in cancer. In this review, we provide a systematic overview of the currently discovered and proven regulatory mechanisms of serine metabolic enzymes in cancer, focusing on three levels: transcriptional, post-transcriptional, and post-translational regulation. Specifically, transcriptional regulation encompasses three major mechanisms: (1) transcription factor-mediated gene expression control, (2) histone modifications, and (3) DNA methylation. At the post-transcriptional level, regulation is primarily achieved through (1) non-coding RNAs, (2) RNA-binding proteins, and (3) RNA modifications. Post-translational regulation is predominantly mediated through diverse protein post-translational modifications. The transcriptional and post-transcriptional mechanisms primarily modulate the expression levels of serine metabolic enzymes, while post-translational modifications exert more diverse effects by altering the activity, protein stability or cellular localization of these enzymes. These regulations collectively modulate serine metabolism to influence tumor progression, offering promising targets for tumor-specific therapeutic interventions.

1. Introduction

Metabolic reprogramming represents a pivotal hallmark of cancer, serving as a critical adaptive mechanism that not only fulfills the heightened bioenergetic and biosynthetic demands of malignant cells, but also modulates tumor microenvironment and resistance to chemotherapy [1]. While the Warburg effect (aerobic glycolysis) remains the prototypical example of oncogenic metabolic adaptation [2], accumulating evidence highlights the critical role of amino acid metabolic rewiring in tumor progression [3]. Particularly noteworthy is that serine metabolism has become a focal point in cancer research due to its pleiotropic regulatory functions, and has been found to be enhanced in multiple cancer types [4]. Serine metabolism encompasses two interconnected branches: de novo serine synthesis and catabolism. The serine synthesis pathway (SSP) converts the glycolytic intermediate 3-phosphoglycerate (3-PG) to serine through sequential catalysis by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) [5]. Conversely, serine catabolism is mediated by serine hydroxymethyltransferase (SHMT), which converts serine to glycine and a one-carbon unit [5]. SHMT exists as two distinct isoforms with compartment-specific localization: SHMT1 in the cytoplasm and SHMT2 in the mitochondria [6].

Serine metabolism plays a pivotal role in tumor metabolic reprogramming, acting as a central node that integrates with multiple metabolic pathways (Figure 1) to support cancer cell proliferation, survival, and adaptation to stress [5]. One of its most prominent connections is with glycolysis. As a major glycolytic intermediate, 3-PG serves as the entry substrate into the SSP, thereby coupling serine biosynthesis directly to glucose catabolism. Serine, in turn, serves as an allosteric activator of pyruvate kinase M2 (PKM2) [7], enhancing glycolytic flux and promoting the Warburg effect. Another crucial amino acid metabolic reprogramming in tumors involves glutamine metabolism, which supplies α-ketoglutarate (α-KG) to the tricarboxylic acid (TCA) cycle. Cytosolic glutaminase converts glutamine to glutamate, while PSAT1 generates both 3-phosphoserine (3-PS) and α-KG through its transaminase activity. The PSAT1-derived α-KG replenishes the TCA cycle to provide reducing equivalents for oxidative phosphorylation (OXPHOS) and adenosine triphosphate (ATP) production, a critical energy source particularly under glutamine blockade conditions [8].