Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation
Abstract Compared to most tumors that are more glycolytic, primary prostate cancer is less glycolytic but more dependent on TCA cycle coupled with OXPHOS for its energy demand. This unique metabolic energetic feature is attributed to activation of mitochondrial m-aconitase in TCA caused by decreased...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07460-z |
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| _version_ | 1850027998226415616 |
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| author | Taiyang Ma Wenjuan Xie Zhenyu Xu Weijie Gao Jianfu Zhou Yuliang Wang Franky Leung Chan |
| author_facet | Taiyang Ma Wenjuan Xie Zhenyu Xu Weijie Gao Jianfu Zhou Yuliang Wang Franky Leung Chan |
| author_sort | Taiyang Ma |
| collection | DOAJ |
| description | Abstract Compared to most tumors that are more glycolytic, primary prostate cancer is less glycolytic but more dependent on TCA cycle coupled with OXPHOS for its energy demand. This unique metabolic energetic feature is attributed to activation of mitochondrial m-aconitase in TCA caused by decreased cellular Zn level. Evidence suggests that a small subpopulation of cancer cells within prostate tumors, designated as prostate cancer stem cells (PCSCs), play significant roles in advanced prostate cancer progression. However, their cellular energetics status is still poorly understood. Nuclear receptor ERRα (ESRRA) is a key regulator of energy metabolism. Previous studies characterize that ERRα exhibits an upregulation in prostate cancer and can perform multiple oncogenic functions. Here, we demonstrate a novel role of ERRα in the control of stemness and energetics metabolism in PCSCs via a mechanism of combined transrepression of Zn transporter ZIP1 in reducing intracellular Zn uptake and transactivation of ACO2 (m-aconitase) in completion of TCA cycle. Results also showed that restoration of Zn accumulation by treatment with a Zn ionophore Clioquinol could significantly suppress both in vitro growth of PCSCs and also their in vivo tumorigenicity, implicating that enhanced cellular Zn uptake could be a potential therapeutic approach for targeting PCSCs in advanced prostate cancer. |
| format | Article |
| id | doaj-art-6c4269332f7b41eabc0e2eced67fddcd |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-6c4269332f7b41eabc0e2eced67fddcd2025-08-20T02:59:57ZengNature Publishing GroupCell Death and Disease2041-48892025-03-0116111610.1038/s41419-025-07460-zEstrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportationTaiyang Ma0Wenjuan Xie1Zhenyu Xu2Weijie Gao3Jianfu Zhou4Yuliang Wang5Franky Leung Chan6School of Biomedical Sciences, The Chinese University of Hong KongSchool of Biomedical Sciences, The Chinese University of Hong KongSchool of Biomedical Sciences, The Chinese University of Hong KongSchool of Biomedical Sciences, The Chinese University of Hong KongSchool of Biomedical Sciences, The Chinese University of Hong KongSchool of Biomedical Sciences, The Chinese University of Hong KongSchool of Biomedical Sciences, The Chinese University of Hong KongAbstract Compared to most tumors that are more glycolytic, primary prostate cancer is less glycolytic but more dependent on TCA cycle coupled with OXPHOS for its energy demand. This unique metabolic energetic feature is attributed to activation of mitochondrial m-aconitase in TCA caused by decreased cellular Zn level. Evidence suggests that a small subpopulation of cancer cells within prostate tumors, designated as prostate cancer stem cells (PCSCs), play significant roles in advanced prostate cancer progression. However, their cellular energetics status is still poorly understood. Nuclear receptor ERRα (ESRRA) is a key regulator of energy metabolism. Previous studies characterize that ERRα exhibits an upregulation in prostate cancer and can perform multiple oncogenic functions. Here, we demonstrate a novel role of ERRα in the control of stemness and energetics metabolism in PCSCs via a mechanism of combined transrepression of Zn transporter ZIP1 in reducing intracellular Zn uptake and transactivation of ACO2 (m-aconitase) in completion of TCA cycle. Results also showed that restoration of Zn accumulation by treatment with a Zn ionophore Clioquinol could significantly suppress both in vitro growth of PCSCs and also their in vivo tumorigenicity, implicating that enhanced cellular Zn uptake could be a potential therapeutic approach for targeting PCSCs in advanced prostate cancer.https://doi.org/10.1038/s41419-025-07460-z |
| spellingShingle | Taiyang Ma Wenjuan Xie Zhenyu Xu Weijie Gao Jianfu Zhou Yuliang Wang Franky Leung Chan Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation Cell Death and Disease |
| title | Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation |
| title_full | Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation |
| title_fullStr | Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation |
| title_full_unstemmed | Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation |
| title_short | Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation |
| title_sort | estrogen related receptor alpha errα controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation |
| url | https://doi.org/10.1038/s41419-025-07460-z |
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