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; Jeremy N Rich

doi:10.1038/s41586-023-06061-0

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Lysine catabolism reprograms tumour immunity through histone crotonylation

Journal article

Peer reviewed

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, …

Nature (London), Vol.617(7962), pp.818-826

05/25/2023

DOI: 10.1038/s41586-023-06061-0

PMCID: PMC11089809

PMID: 37198486

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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 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.

Animals

Chromatin - chemistry

Chromatin - genetics

Chromatin - metabolism

Glutaryl-CoA Dehydrogenase - metabolism

Histones - chemistry

Histones - metabolism

Humans

Interferon Type I - immunology

Lysine - deficiency

Lysine - metabolism

Mice

Neoplasms - drug therapy

Neoplasms - immunology

Neoplasms - metabolism

Neoplasms - pathology

Protein Processing, Post-Translational

RNA, Double-Stranded - immunology

Details

Title: Subtitle: Lysine catabolism reprograms tumour immunity through histone crotonylation
Creators: Huairui Yuan - UPMC Hillman Cancer Center
Xujia Wu - University of Pittsburgh Medical Center
Qiulian Wu - University of Pittsburgh Medical Center
Adam Chatoff - Temple University
Emily Megill - Temple University
Jinjun Gao - University of Chicago
Tengfei Huang - University of Pittsburgh Medical Center
Tingting Duan - University of Pittsburgh Medical Center
Kailin Yang - Cleveland Clinic
Chunyu Jin - University of California San Diego
Fanen Yuan - University of Pittsburgh Medical Center
Shuai Wang - UPMC Hillman Cancer Center
Linjie Zhao - University of Pittsburgh Medical Center
Pascal O Zinn - University of Pittsburgh Medical Center
Kalil G Abdullah - UPMC Hillman Cancer Center
Yingming Zhao - University of Chicago
Nathaniel W Snyder - Temple University
Jeremy N Rich - University of Pittsburgh Medical Center
Resource Type: Journal article
Publication Details: Nature (London), Vol.617(7962), pp.818-826
DOI: 10.1038/s41586-023-06061-0
PMID: 37198486
PMCID: PMC11089809
NLM abbreviation: Nature
ISSN: 0028-0836
eISSN: 1476-4687
Grant note: R01 AR078555 / NIAMS NIH HHS R01 GM135504 / NIGMS NIH HHS R01 CA251677 / NCI NIH HHS R35 CA197718 / NCI NIH HHS R01 GM132261 / NIGMS NIH HHS R01 CA238662 / NCI NIH HHS R01 NS103434 / NINDS NIH HHS
Language: English
Date published: 05/25/2023
Academic Unit: Radiation Oncology
Record Identifier: 9984696718702771

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