Lysine catabolism reprograms tumour immunity through histone crotonylation

Huairui Yuan, Xujia Wu, Qiulian Wu, Adam Chatoff, Emily Megill, Jinjun Gao, Tengfei Huang, Tingting Duan, Kailin Yang, Chunyu Jin, Fanen Yuan, Shuai Wang, Linjie Zhao, Pascal O. Zinn, Kalil G. Abdullah, Yingming Zhao, Nathaniel W. Snyder and Jeremy N. Rich ()
Additional contact information
Huairui Yuan: University of Pittsburgh Medical Center
Xujia Wu: University of Pittsburgh Medical Center
Qiulian Wu: University of Pittsburgh Medical Center
Adam Chatoff: Lewis Katz School of Medicine at Temple University
Emily Megill: Lewis Katz School of Medicine at Temple University
Jinjun Gao: The University of Chicago
Tengfei Huang: University of Pittsburgh Medical Center
Tingting Duan: University of Pittsburgh Medical Center
Kailin Yang: Taussig Cancer Center, Cleveland Clinic
Chunyu Jin: University of California
Fanen Yuan: University of Pittsburgh Medical Center
Shuai Wang: University of Pittsburgh Medical Center
Linjie Zhao: University of Pittsburgh Medical Center
Pascal O. Zinn: University of Pittsburgh Medical Center
Kalil G. Abdullah: University of Pittsburgh Medical Center
Yingming Zhao: The University of Chicago
Nathaniel W. Snyder: Lewis Katz School of Medicine at Temple University
Jeremy N. Rich: University of Pittsburgh Medical Center

Nature, 2023, vol. 617, issue 7962, 818-826

Abstract: Abstract Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment1,2. Lysine functions as a biosynthetic molecule, energy source and antioxidant3–5, 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 CD8+ T 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.

Date: 2023
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06061-0 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:617:y:2023:i:7962:d:10.1038_s41586-023-06061-0

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06061-0

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().