Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression
Ferroptosis has emerged to be a promising approach in cancer therapies; however, colorectal cancer (CRC) is relatively insensitive to ferroptosis. Exactly how the gut microenvironment impacts the ferroptotic sensitivity of CRC remains unknown. Herein, by performing metabolomics, we discovered that b...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723002239 |
| _version_ | 1828717392719511552 |
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| author | Ying He Yuhang Ling Zhiyong Zhang Randall Tyler Mertens Qian Cao Xutao Xu Ke Guo Qian Shi Xilin Zhang Lixia Huo Kan Wang Huihui Guo Weiyun Shen Manlu Shen Wenming Feng Peng Xiao |
| author_facet | Ying He Yuhang Ling Zhiyong Zhang Randall Tyler Mertens Qian Cao Xutao Xu Ke Guo Qian Shi Xilin Zhang Lixia Huo Kan Wang Huihui Guo Weiyun Shen Manlu Shen Wenming Feng Peng Xiao |
| author_sort | Ying He |
| collection | DOAJ |
| description | Ferroptosis has emerged to be a promising approach in cancer therapies; however, colorectal cancer (CRC) is relatively insensitive to ferroptosis. Exactly how the gut microenvironment impacts the ferroptotic sensitivity of CRC remains unknown. Herein, by performing metabolomics, we discovered that butyrate concentrations were significantly decreased in CRC patients. Butyrate supplementation sensitized CRC mice to ferroptosis induction, showing great in vivo translatability. Particularly, butyrate treatment reduced ferroptotic resistance of cancer stem cells. Mechanistically, butyrate inhibited xCT expression and xCT-dependent glutathione synthesis. Moreover, we identified c-Fos as a novel xCT suppressor, and further elucidated that butyrate induced c-Fos expression via disrupting class I HDAC activity. In CRC patients, butyrate negatively correlated with tumor xCT expression and positively correlated with c-Fos expression. Finally, butyrate was found to boost the pro-ferroptotic function of oxaliplatin (OXA). Immunohistochemistry data showed that OXA non-responders exhibited higher xCT expression compared to OXA responders. Hence, butyrate supplementation is a promising approach to break the ferroptosis resistance in CRC. |
| first_indexed | 2024-03-12T14:27:42Z |
| format | Article |
| id | doaj.art-cac2850a23a54970b4e1ba767a36ecb0 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-12T14:27:42Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-cac2850a23a54970b4e1ba767a36ecb02023-08-18T04:31:05ZengElsevierRedox Biology2213-23172023-09-0165102822Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppressionYing He0Yuhang Ling1Zhiyong Zhang2Randall Tyler Mertens3Qian Cao4Xutao Xu5Ke Guo6Qian Shi7Xilin Zhang8Lixia Huo9Kan Wang10Huihui Guo11Weiyun Shen12Manlu Shen13Wenming Feng14Peng Xiao15Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, ChinaCentral Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, ChinaDepartment of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, ChinaDepartment of Immunology, Harvard Medical School, Boston, 02120, USADepartment of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China; Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, ChinaCentral Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, ChinaCentral Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, ChinaCentral Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, ChinaCentral Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, ChinaCentral Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, ChinaCentral Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, China; Corresponding author. Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China.Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China; Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China; Institute of Immunology, Zhejiang University School of Medicine, 310058, Hangzhou, China; The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, 310058, China; Corresponding author. Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.Ferroptosis has emerged to be a promising approach in cancer therapies; however, colorectal cancer (CRC) is relatively insensitive to ferroptosis. Exactly how the gut microenvironment impacts the ferroptotic sensitivity of CRC remains unknown. Herein, by performing metabolomics, we discovered that butyrate concentrations were significantly decreased in CRC patients. Butyrate supplementation sensitized CRC mice to ferroptosis induction, showing great in vivo translatability. Particularly, butyrate treatment reduced ferroptotic resistance of cancer stem cells. Mechanistically, butyrate inhibited xCT expression and xCT-dependent glutathione synthesis. Moreover, we identified c-Fos as a novel xCT suppressor, and further elucidated that butyrate induced c-Fos expression via disrupting class I HDAC activity. In CRC patients, butyrate negatively correlated with tumor xCT expression and positively correlated with c-Fos expression. Finally, butyrate was found to boost the pro-ferroptotic function of oxaliplatin (OXA). Immunohistochemistry data showed that OXA non-responders exhibited higher xCT expression compared to OXA responders. Hence, butyrate supplementation is a promising approach to break the ferroptosis resistance in CRC.http://www.sciencedirect.com/science/article/pii/S2213231723002239Colorectal cancerButyrateFerroptosisxCTc-Fos |
| spellingShingle | Ying He Yuhang Ling Zhiyong Zhang Randall Tyler Mertens Qian Cao Xutao Xu Ke Guo Qian Shi Xilin Zhang Lixia Huo Kan Wang Huihui Guo Weiyun Shen Manlu Shen Wenming Feng Peng Xiao Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression Redox Biology Colorectal cancer Butyrate Ferroptosis xCT c-Fos |
| title | Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression |
| title_full | Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression |
| title_fullStr | Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression |
| title_full_unstemmed | Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression |
| title_short | Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression |
| title_sort | butyrate reverses ferroptosis resistance in colorectal cancer by inducing c fos dependent xct suppression |
| topic | Colorectal cancer Butyrate Ferroptosis xCT c-Fos |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723002239 |
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