The role of RNA alternative splicing in regulating cancer metabolism

Abstract

Tumor cells alter their metabolism by a wide array of mechanisms to promote growth and proliferation. Dysregulated expression and/or somatic mutations of key components of the glycolytic pathway/TCA cycle as well as other metabolic pathways allow tumor cells to improve their ability to survive harsh conditions such as hypoxia and the presence of reactive oxygen species, as well as the ability to obtain nutrients to increase lipids, protein, and nucleic acids biogenesis. Approximately 95% of the human protein encoding genes undergo alternative splicing (AS), a regulated process of gene expression that greatly diversifies the proteome by creating multiple proteins from a single gene. In recent years, a growing body of evidence suggests that unbalanced AS, the formation of certain pro-tumorigenic isoforms and the reduction of anti-tumorigenic isoforms, is implicated in a variety of cancers. It is becoming increasingly clear that cancer-associated AS contributes to increased growth and proliferation, partially due to effects on metabolic reprogramming. Here, we summarize the known roles of AS in regulating cancer metabolism. We present evidence supporting the idea that AS, in many types of cancer, acts as a molecular switch that alters metabolism to drive tumorigenesis. We propose that the elucidation of misregulated AS and its downstream effects on cancer metabolism emphasizes the need for new therapeutic approaches aiming to modulate the splicing machinery to selectively target cancer cells.