Ubiquitination in lipid metabolism reprogramming: implications for pediatric solid tumors

Abstract

Pediatric solid tumors represent a significant subset of childhood cancers, accounting for approximately 60% of new diagnoses. Despite advancements in therapeutic strategies, survival rates remain markedly disparate between high-income and resource-limited settings, underscoring the urgent need for novel and effective treatments. Lipid metabolic reprogramming is a fundamental hallmark of cancer, driving tumor progression, therapeutic resistance, and immune evasion through enhanced fatty acid uptake, increased de novo lipid synthesis, and activated fatty acid β-oxidation (FAO). Ubiquitination, a dynamic post-translational modification mediated by the ubiquitin-proteasome system (UPS), plays a crucial role in regulating lipid metabolism by modulating the stability and activity of key metabolic enzymes and transporters involved in cholesterol and fatty acid pathways. This review comprehensively examines the complex interplay between ubiquitination and lipid metabolic reprogramming in pediatric solid tumors. It delineates the mechanisms by which ubiquitination influences cholesterol biosynthesis, uptake, efflux, and fatty acid synthesis and oxidation, thereby facilitating tumor growth and survival. Furthermore, the review identifies potential UPS-mediated therapeutic targets and explores the feasibility of integrating ubiquitination-based strategies with existing treatments. By targeting the UPS to disrupt lipid metabolism pathways, novel therapeutic avenues may emerge to enhance treatment efficacy and overcome resistance in pediatric oncology. This synthesis of current knowledge aims to provide a foundation for the development of innovative, precision medicine approaches to improve clinical outcomes for children afflicted with solid tumors.

Keywords: cholesterol biosynthesis; fatty acid β-oxidation; lipid metabolism; pediatric solid tumor; ubiquitin-proteasome system (UPS).

Figure 1

Ubiquitination and fatty acid (FA) metabolism in pediatric cancers. (Created in https://BioRender.com.) FA metabolism is driven by key enzymes and regulators, many of which are subject to ubiquitination and deubiquitination, marked in orange and green boxes, respectively. Sterol regulatory element-binding protein 1 (SREBP1) plays a central role in regulating FA synthesis. It is ubiquitinated by the Skp1-Cul1-FBW7 (SCF^FBW7) E3 ligase complex and Ring Finger Protein 20 (RNF20). Stabilized expression of SREBP1 promotes tumor progression. FA also activates peroxisome proliferator-activated receptors (PPARs), which are fine-tuned by UPS. PPAR activation induces the expression of cluster of differentiation 36 (CD36), a receptor involved in FA uptake. CD36, regulated by PARKIN-dependent ubiquitination, is associated with tumor progression, immune evasion, and metastasis in pediatric cancers, correlating with poor prognosis. However, the TSP-1/CD36 axis can inhibit angiogenesis under certain conditions. Internalized free fatty acids (FFAs) are converted into monoglycerides (MGs), diglycerides (DGs), and triglycerides (TGs), which are stored in lipid droplets (LDs). Upon energy demand, TGs are hydrolyzed by adipose triglyceride lipase (ATGL), which is ubiquitinated by COP1 and RNF213. FFAs can also be used to generate unsaturated fatty acids (e.g., MUFAs and PUFAs), a process requiring carnitine palmitoyltransferase 2 (CPT2), ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), and fatty acid-binding proteins FABP4 and FABP5. CPT2 is essential for FA transport into mitochondria. These enzymes (CPT2, ACLY, ACC, FASN, SCD1, FABP4, and FABP5) are frequently overexpressed in pediatric cancers and are drivers of tumor progression and poor prognosis.

Figure 2

The role of ubiquitination in cholesterol metabolism and tumor prognosis. Cholesterol uptake: LDL receptor (LDLR) mediates cholesterol uptake. PCSK9 promotes LDLR degradation via the lysosome, while the E3 ubiquitin ligase IDOL ubiquitinates LDLR, targeting it for proteasomal degradation, reducing cholesterol uptake; Cholesterol Synthesis: The rate-limiting enzyme HMG-CoA reductase (HMGCR) is ubiquitinated by RNF145, gp78, HRD1, and RNF139, leading to degradation. Squalene epoxidase (SQLE) is ubiquitinated by MARCH6, affecting cholesterol biosynthesis; Cholesterol Efflux: ATP-binding cassette transporters ABCA1 and ABCG1 mediate cholesterol efflux. Their regulation involves ubiquitination by HUWE1, NEDD4-1, and others; Cholesterol Esterification: Acyl-CoA:cholesterol acyltransferase (ACAT) facilitates cholesterol storage in lipid droplets (LDs), regulated by gp78 and UPS19; Transcriptional Regulation: The sterol regulatory element-binding protein (SREBP) pathway controls cholesterol biosynthesis. SCAP facilitates SREBP transport from the ER to the Golgi, where it is activated. The INSIG-SCAP-SREBP complex is regulated via ubiquitination by gp78 and TRC8, while RNF145 and RNF5 ubiquitinate SCAP to modulate its stability. LXR activation induces genes like ABCA1, ABCG1, and IDOL, affecting cholesterol homeostasis. Cancer Metabolism and Prognostic Markers: EGFR signaling and glucose metabolism enhance SREBP activation, contributing to tumor lipid metabolism. Ubiquitination (orange boxes) and deubiquitination (green boxes) modulate key enzymes and pathways, influencing tumor progression and prognosis. Markers with red arrows (↑,↓) indicate prognostic impact, where upregulated elements are linked to poor prognosis, while downregulated components improve prognosis.