2. Academic Validation
  3. The m6A modification-mediated OGDHL exerts a tumor suppressor role in ccRCC by downregulating FASN to inhibit lipid synthesis and ERK signaling

The m6A modification-mediated OGDHL exerts a tumor suppressor role in ccRCC by downregulating FASN to inhibit lipid synthesis and ERK signaling

  • Cell Death Dis. 2023 Aug 25;14(8):560. doi: 10.1038/s41419-023-06090-7.
Jian Shi # 1 2,  Daojia Miao # 1 2,  Qingyang Lv # 1 2,  Keshan Wang 1 2,  Qi Wang 1 2,  Huageng Liang 1 2,  Hongmei Yang 3,  Zhiyong Xiong 4 5,  Xiaoping Zhang 6 7
Affiliations

Affiliations

  • 1 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, P.R. China.
  • 2 Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, P.R. China.
  • 3 Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, P.R. China. hyang@hust.edu.cn.
  • 4 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, P.R. China. tjxiongzhiyong@163.com.
  • 5 Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, P.R. China. tjxiongzhiyong@163.com.
  • 6 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, P.R. China. xzhang@hust.edu.cn.
  • 7 Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, P.R. China. xzhang@hust.edu.cn.
  • # Contributed equally.
PMID: 37626050 DOI: 10.1038/s41419-023-06090-7
Abstract

Metabolic reprogramming is a hallmark of Cancer, and the impact of lipid metabolism as a crucial aspect of metabolic reprogramming on clear cell renal cell carcinoma (ccRCC) progression has been established. However, the regulatory mechanisms underlying the relationship between metabolic abnormalities and ccRCC progression remain unclear. Therefore, this study aimed to identify key regulatory factors of metabolic reprogramming in ccRCC and provide potential therapeutic targets for ccRCC patients. Potential metabolic regulatory factors in ccRCC were screened using bioinformatics analysis. Public databases and patient samples were used to investigate the aberrant expression of Oxoglutarate dehydrogenase-like (OGDHL) in ccRCC. The function of OGDHL in ccRCC growth and metastasis was evaluated through in vitro and in vivo functional experiments. Mechanistic insights were obtained through luciferase reporter assays, chromatin immunoprecipitation, RNA methylation immunoprecipitation, and mutagenesis studies. OGDHL mRNA and protein levels were significantly downregulated in ccRCC tissues. Upregulation of OGDHL expression effectively inhibited ccRCC growth and metastasis both in vitro and in vivo. Furthermore, FTO-mediated OGDHL m6A demethylation suppressed its expression in ccRCC. Mechanistically, low levels of OGDHL promoted TFAP2A expression by inhibiting ubiquitination levels, which then bound to the FASN promoter region and transcriptionally activated FASN expression, thereby promoting lipid accumulation and ERK pathway activation. Our findings demonstrate the impact of OGDHL on ccRCC progression and highlight the role of the FTO/OGDHL/TFAP2A/FASN axis in regulating ccRCC lipid metabolism and progression, providing new targets for ccRCC therapy.

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