Abstract
Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment. Lysine functions as a biosynthetic molecule, energy source and antioxidant, but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP-AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.
Overview
- The study investigates the role of lysine in glioblastoma stem cells (GSCs) and its impact on tumor growth and microenvironment reshaping. The hypothesis being tested is that GSCs reprogram lysine catabolism to generate specialized metabolites that support tumor growth and evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response. The methodology used includes genetic manipulation, lysine restriction, and analysis of intracellular metabolites and chromatin landscape. The primary objective of the study is to understand the pathological role of lysine in cancer and identify potential therapeutic targets for GSCs.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions, including genetic manipulation, lysine restriction, and anti-PD-1 therapy. The results show that a reduction in histone lysine crotonylation by genetic manipulation or lysine restriction impaired tumor growth and promoted immunogenic cytosolic dsRNA and dsDNA generation. Additionally, a lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumor growth. The key findings of the study suggest that GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodeling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice, as they suggest that targeting lysine metabolism in GSCs could be a potential therapeutic approach for glioblastoma. However, the study also identifies limitations, such as the need for further investigation of the specific mechanisms underlying the effects of lysine restriction on GSCs. Future research directions could include exploring the role of other amino acids in GSC metabolism and identifying additional therapeutic targets for glioblastoma. The study highlights the importance of understanding the metabolic adaptations of cancer cells and the potential for targeting these adaptations for therapeutic benefit.