Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression
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
Affiliations
Ying He
Central 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
Yuhang Ling
Central 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
Zhiyong Zhang
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
Randall Tyler Mertens
Department of Immunology, Harvard Medical School, Boston, 02120, USA
Qian Cao
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
Xutao Xu
Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
Ke Guo
Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
Qian Shi
Central 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
Xilin Zhang
Central 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
Lixia Huo
Central 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
Kan Wang
Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
Huihui Guo
Central 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
Weiyun Shen
Central 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
Manlu Shen
Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
Wenming Feng
Central 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.
Peng Xiao
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.
