Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia
Previous studies have shown that inhibition of TNF family member FN14 (gene: <i>TNFRSF12A</i>) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear....
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/9/1818 |
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| author | Bryan I. Ruiz Xazmin H. Lowman Ying Yang Qi Fan Tianhong Wang Hongmei Wu Eric A. Hanse Mei Kong |
| author_facet | Bryan I. Ruiz Xazmin H. Lowman Ying Yang Qi Fan Tianhong Wang Hongmei Wu Eric A. Hanse Mei Kong |
| author_sort | Bryan I. Ruiz |
| collection | DOAJ |
| description | Previous studies have shown that inhibition of TNF family member FN14 (gene: <i>TNFRSF12A</i>) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that <i>TNFRSF12A</i> expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted <i>TNFRSF12A</i> induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the <i>Tnfrsf12a</i> promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of <i>Tnfrsf12a</i> and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model. These findings highlight a connection between metabolic stress and cancer cachexia development. |
| first_indexed | 2024-03-10T22:43:53Z |
| format | Article |
| id | doaj.art-f2baf32245ca4c4aa44c21e232045676 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T22:43:53Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
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| series | Genes |
| spelling | doaj.art-f2baf32245ca4c4aa44c21e2320456762023-11-19T10:54:07ZengMDPI AGGenes2073-44252023-09-01149181810.3390/genes14091818Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced CachexiaBryan I. Ruiz0Xazmin H. Lowman1Ying Yang2Qi Fan3Tianhong Wang4Hongmei Wu5Eric A. Hanse6Mei Kong7Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USADepartment of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USADepartment of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USADepartment of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USADepartment of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USADepartment of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USADepartment of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USADepartment of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USAPrevious studies have shown that inhibition of TNF family member FN14 (gene: <i>TNFRSF12A</i>) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that <i>TNFRSF12A</i> expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted <i>TNFRSF12A</i> induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the <i>Tnfrsf12a</i> promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of <i>Tnfrsf12a</i> and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model. These findings highlight a connection between metabolic stress and cancer cachexia development.https://www.mdpi.com/2073-4425/14/9/1818cancercachexiacolon cancerFN14<i>TNFRSF12A</i>alpha-ketoglutarate |
| spellingShingle | Bryan I. Ruiz Xazmin H. Lowman Ying Yang Qi Fan Tianhong Wang Hongmei Wu Eric A. Hanse Mei Kong Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia Genes cancer cachexia colon cancer FN14 <i>TNFRSF12A</i> alpha-ketoglutarate |
| title | Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia |
| title_full | Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia |
| title_fullStr | Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia |
| title_full_unstemmed | Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia |
| title_short | Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia |
| title_sort | alpha ketoglutarate regulates tnfrsf12a fn14 expression via histone modification and prevents cancer induced cachexia |
| topic | cancer cachexia colon cancer FN14 <i>TNFRSF12A</i> alpha-ketoglutarate |
| url | https://www.mdpi.com/2073-4425/14/9/1818 |
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