Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis
Abstract Whereas it is appreciated that cancer cells rewire lipid metabolism to survive and propagate, the roles of lipid metabolism in metastasis remain largely unknown. In this study, using esophageal squamous cell carcinoma (ESCC) as a pulmonary metastasis model, we find that the enzyme fatty aci...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-10-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-022-01199-1 |
| _version_ | 1811257115938914304 |
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| author | Xuantong Zhou Furong Huang Gang Ma Wenqing Wei Nan Wu Zhihua Liu |
| author_facet | Xuantong Zhou Furong Huang Gang Ma Wenqing Wei Nan Wu Zhihua Liu |
| author_sort | Xuantong Zhou |
| collection | DOAJ |
| description | Abstract Whereas it is appreciated that cancer cells rewire lipid metabolism to survive and propagate, the roles of lipid metabolism in metastasis remain largely unknown. In this study, using esophageal squamous cell carcinoma (ESCC) as a pulmonary metastasis model, we find that the enzyme fatty acid 2-hydroxylase (FA2H), which catalyzes the hydroxylation of free fatty acids (FAs), is enriched in a subpopulation of ESCC cells with high metastatic potential, and that FA2H knockdown markedly mitigates metastatic lesions. Moreover, increased FA2H expression is positively associated with poor survival in patients with ESCC. Lipidomics analysis identifies that two dihydroceramides—Cer(d18:0/24:0) and Cer(d18:0/24:1)—are increased in FA2H-depleted metastasizing ESCC cells. Upon administration, Cer(d18:0/24:0) and Cer(d18:0/24:1) impair the formation of overt metastases in a mouse experimental metastasis model. Then, forkhead box protein C2 (FOXC2) and FA2H are found to be co-upregulated in metastatic ESCC cell populations and ESCC specimens, and FA2H expression is further experimentally verified to be transcriptionally induced by FOXC2, which is boosted per se by tumour necrosis factor α (TNFα), a critical pro-metastasis cytokine in the tumour microenvironment, in metastasizing cells. Together, these results demonstrate that TNFα-FOXC2-FA2H is a novel signaling axis to promote metastasis, and its downstream dihydroceramide products could be promising drugs to intervene in metastasis. |
| first_indexed | 2024-04-12T17:51:32Z |
| format | Article |
| id | doaj.art-1e2e8f6edb414b80bf21c17d965899fb |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-12T17:51:32Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-1e2e8f6edb414b80bf21c17d965899fb2022-12-22T03:22:29ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352022-10-017111410.1038/s41392-022-01199-1Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasisXuantong Zhou0Furong Huang1Gang Ma2Wenqing Wei3Nan Wu4Zhihua Liu5State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for CancerState Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II, Peking University Cancer Hospital & InstituteState Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract Whereas it is appreciated that cancer cells rewire lipid metabolism to survive and propagate, the roles of lipid metabolism in metastasis remain largely unknown. In this study, using esophageal squamous cell carcinoma (ESCC) as a pulmonary metastasis model, we find that the enzyme fatty acid 2-hydroxylase (FA2H), which catalyzes the hydroxylation of free fatty acids (FAs), is enriched in a subpopulation of ESCC cells with high metastatic potential, and that FA2H knockdown markedly mitigates metastatic lesions. Moreover, increased FA2H expression is positively associated with poor survival in patients with ESCC. Lipidomics analysis identifies that two dihydroceramides—Cer(d18:0/24:0) and Cer(d18:0/24:1)—are increased in FA2H-depleted metastasizing ESCC cells. Upon administration, Cer(d18:0/24:0) and Cer(d18:0/24:1) impair the formation of overt metastases in a mouse experimental metastasis model. Then, forkhead box protein C2 (FOXC2) and FA2H are found to be co-upregulated in metastatic ESCC cell populations and ESCC specimens, and FA2H expression is further experimentally verified to be transcriptionally induced by FOXC2, which is boosted per se by tumour necrosis factor α (TNFα), a critical pro-metastasis cytokine in the tumour microenvironment, in metastasizing cells. Together, these results demonstrate that TNFα-FOXC2-FA2H is a novel signaling axis to promote metastasis, and its downstream dihydroceramide products could be promising drugs to intervene in metastasis.https://doi.org/10.1038/s41392-022-01199-1 |
| spellingShingle | Xuantong Zhou Furong Huang Gang Ma Wenqing Wei Nan Wu Zhihua Liu Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis Signal Transduction and Targeted Therapy |
| title | Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis |
| title_full | Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis |
| title_fullStr | Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis |
| title_full_unstemmed | Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis |
| title_short | Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis |
| title_sort | dysregulated ceramides metabolism by fatty acid 2 hydroxylase exposes a metabolic vulnerability to target cancer metastasis |
| url | https://doi.org/10.1038/s41392-022-01199-1 |
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