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  3. NSUN5/TET2-directed chromatin-associated RNA modification of 5-methylcytosine to 5-hydroxymethylcytosine governs glioma immune evasion

NSUN5/TET2-directed chromatin-associated RNA modification of 5-methylcytosine to 5-hydroxymethylcytosine governs glioma immune evasion

  • Proc Natl Acad Sci U S A. 2024 Apr 2;121(14):e2321611121. doi: 10.1073/pnas.2321611121.
Ruixin Wu # 1 2,  Chunming Sun # 1 3,  Xi Chen # 1,  Runyue Yang # 1 4,  Yuxuan Luan 1 5,  Xiang Zhao 1,  Panpan Yu 1,  Rongkui Luo 6,  Yingyong Hou 6,  Ruotong Tian 1,  Shasha Bian 1 5,  Yuli Li 1,  Yinghua Dong 1 7,  Qian Liu 1,  Weiwei Dai 1 5,  Zhuoyang Fan 1,  Rucheng Yan 1,  Binyang Pan 1 2,  Siheng Feng 1,  Jing Wu 1 2,  Fangzhen Chen 1 2,  Changle Yang 1 2,  Hanlin Wang 1,  Haochen Dai 1,  Minfeng Shu 1 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 2 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 3 Department of Neurology, Huashan hospital, Fudan University, Shanghai 200040, China.
  • 4 Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 5 Department of Microbiology, Key Laboratory of Medical Molecular Virology (Ministry of Education/ National Health Commission/ Chinese Academy of Medical Sciences), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 6 Department of Pathology, Zhongshan hospital, Fudan University, Shanghai 200032, China.
  • 7 Department of Logistics, Dalian No.3 People's hospital Affiliated to Dalian Medical University, Dalian 116033, China.
  • # Contributed equally.
PMID: 38547058 DOI: 10.1073/pnas.2321611121
Abstract

Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates β-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of β-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy.

Keywords

CTNNB1; NSUN5; RBFOX2; RNA methylation; glioma.

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