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GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Nguyen, Tin Tin Manh | - |
dc.contributor.author | Nguyen, Thi Ha | - |
dc.contributor.author | Kim, Han Sun | - |
dc.contributor.author | Dao, Thien T. P. | - |
dc.contributor.author | Moon, Yechan | - |
dc.contributor.author | Seo, Munjun | - |
dc.contributor.author | Kang, Sunmi | - |
dc.contributor.author | Mai, Van-Hieu | - |
dc.contributor.author | An, Yong Jin | - |
dc.contributor.author | Jung, Cho-Rok | - |
dc.contributor.author | Kim, Jin-Mo | - |
dc.contributor.author | Park, Sunghyouk | - |
dc.date.accessioned | 2023-05-11T08:19:20Z | - |
dc.date.available | 2023-05-11T17:20:14Z | - |
dc.date.issued | 2023-02-07 | - |
dc.identifier.citation | Journal of Experimental & Clinical Cancer Research, 42(1):42 | ko_KR |
dc.identifier.issn | 1756-9966 | - |
dc.identifier.uri | https://hdl.handle.net/10371/192380 | - |
dc.description.abstract | Background
Clear cell renal cell carcinoma (ccRCC), with its hallmark phenotype of high cytosolic lipid content, is considered a metabolic cancer. Despite the implication of this lipid-rich phenotype in ccRCC tumorigenesis, the roles and regulators of de novo lipid synthesis (DNL) in ccRCC remain largely unexplained. Methods Our bioinformatic screening focused on ccRCC-lipid phenotypes identified glutathione peroxidase 8 (GPX8), as a clinically relevant upstream regulator of DNL. GPX8 genetic silencing was performed with CRISPR-Cas9 or shRNA in ccRCC cell lines to dissect its roles. Untargeted metabolomics, RNA-seq analyses, and other biochemical assays (e.g., lipid droplets staining, fatty acid uptake, cell proliferation, xenograft, etc.) were carried out to investigate the GPX8s involvement in lipid metabolism and tumorigenesis in ccRCC. The lipid metabolic function of GPX8 and its downstream were also measured by isotope-tracing-based DNL flux measurement. Results GPX8 knockout or downregulation substantially reduced lipid droplet levels (independent of lipid uptake), fatty acid de novo synthesis, triglyceride esterification in vitro, and tumor growth in vivo. The downstream regulator was identified as nicotinamide N-methyltransferase (NNMT): its knockdown phenocopied, and its expression rescued, GPX8 silencing both in vitro and in vivo. Mechanically, GPX8 regulated NNMT via IL6-STAT3 signaling, and blocking this axis suppressed ccRCC survival by activating AMPK. Notably, neither the GPX8-NNMT axis nor the DNL flux was affected by the von Hippel Lindau (VHL) status, the conventional regulator of ccRCC high lipid content. Conclusions Taken together, our findings unravel the roles of the VHL-independent GPX8-NNMT axis in ccRCC lipid metabolism as related to the phenotypes and growth of ccRCC, which may be targeted for therapeutic purposes. Graphical abstract | ko_KR |
dc.description.sponsorship | The research was supported by the Basic Science Research Program (grant NRF-2018R1A3B1052328 to S.P.) funded by the Ministry of Science, Information and Communication Technology, by Future Planning through the National Research Foundation, and by the Basic Science Research Program through the National Research Foundation (NRF-2020R1I1A1A01073124 to J-M.K.) funded by the Ministry of Education of Korea. | ko_KR |
dc.language.iso | en | ko_KR |
dc.publisher | BMC | ko_KR |
dc.subject | Clear cell renal cell carcinoma (ccRCC) | - |
dc.subject | GPX8 | - |
dc.subject | NNMT | - |
dc.subject | AMPK | - |
dc.subject | De novo lipogenesis (DNL) | - |
dc.title | GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT | ko_KR |
dc.type | Article | ko_KR |
dc.identifier.doi | 10.1186/s13046-023-02607-2 | ko_KR |
dc.citation.journaltitle | Journal of Experimental & Clinical Cancer Research | ko_KR |
dc.language.rfc3066 | en | - |
dc.rights.holder | The Author(s) | - |
dc.date.updated | 2023-03-30T09:53:10Z | - |
dc.citation.number | 42 | ko_KR |
dc.citation.volume | 42 | ko_KR |
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