Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma

• Published in: Cell death & disease 2024-02, Vol.15 (2), p.151-9, Article 151
• Main Authors: Zhu, Liangsong, Hong, Yilun, Zhu, Ziran, Huang, Jiwei, Wang, Jianfeng, Li, Ge, Wu, Xiaoyu, Chen, Yonghui, Xu, Yunze, Zheng, Liang, Huang, Yiran, Kong, Wen, Xue, Wei, Zhang, Jin
• Format: Article
• Language: English
• Subjects: 13/105; 13/106; 13/51; 13/89; 38; 38/1; 38/23; 38/32; 38/61; 38/91; 631/67; 631/80; Animal models; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Biology; Cell Culture; Cell proliferation; Demethylation; Experiments; Fumarase; Fumarates - metabolism; Gene deletion; Glutamine; Histones; Humans; Immunology; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Life Sciences; Mass spectrometry; Mass spectroscopy; Metabolic disorders; Metabolism; Mice; Molecular modelling; Non-coding RNA; Renal cell carcinoma; RNA, Long Noncoding - genetics; Scientific imaging; Stat1 protein; Therapeutic targets; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06510-2

Fumarate hydratase (FH) deficient renal cell carcinoma (RCC) is a type of tumor with definite metabolic disorder, but the mechanism of metabolic remodeling is still unclear. LncRNA was reported to closely correlate with cancer metabolism, however the biological role of LncRNA in the development of progression of FH-deficent RCC was not well studied either. FH-deficient RCC samples were collected in my hospital and used for RNA-sequencing and Mass spectrometry analysis. FH-deficient RCC cell line UOK262 and control pFH cells were used for in vitro experiments, including proliferation assay, transwell assay, western-blot, mass spectrometry and so on. PDX mouse model was used for further drug inhibition experiments in vivo. In this study, we analyzed the profiles of LncRNA and mRNA in FH-deficienct RCC samples, and we found that the LncRNA-MIR4435-2GH was specifically highly expressed in FH-deficient RCC compared with ccRCC. In vitro experiments demonstrated that MIR4435-2HG was regulated by Fumarate through histone demethylation, and the deletion of this gene could inhibit glutamine metabolism. RNA-pulldown experiments showed that MIR4435-2HG specifically binds to STAT1, which can transcriptionally activate GLS1. GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.