Lysine catabolism reprograms tumour immunity through histone crotonylation

Nature. 2023 May;617(7962):818-826. doi: 10.1038/s41586-023-06061-0.

Huairui Yuan ¹, Xujia Wu ¹, Qiulian Wu ¹, Adam Chatoff ², Emily Megill ², Jinjun Gao ³, Tengfei Huang ¹, Tingting Duan ¹, Kailin Yang ⁴, Chunyu Jin ⁵, Fanen Yuan ¹, Shuai Wang ¹, Linjie Zhao ¹, Pascal O Zinn ¹ ⁶, Kalil G Abdullah ¹ ⁶, Yingming Zhao ³, Nathaniel W Snyder ², Jeremy N Rich ⁷ ⁸

Affiliations

1 Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
2 Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
3 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
4 Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
5 Department and School of Medicine, University of California, San Diego, CA, USA.
6 Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
7 Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. [email protected].
8 Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. [email protected].

PMID: 37198486 DOI: 10.1038/s41586-023-06061-0

Abstract

Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment^1,2. Lysine functions as a biosynthetic molecule, energy source and antioxidant^3-5, 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.

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