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

doi:10.1016/j.redox.2023.102822

Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression

Redox Biol. 2023 Sep:65:102822. doi: 10.1016/j.redox.2023.102822. Epub 2023 Jul 20.

Authors

Ying He¹, Yuhang Ling¹, Zhiyong Zhang², Randall Tyler Mertens³, Qian Cao⁴, Xutao Xu⁵, Ke Guo⁵, Qian Shi¹, Xilin Zhang¹, Lixia Huo¹, Kan Wang⁵, Huihui Guo¹, Weiyun Shen¹, Manlu Shen⁵, Wenming Feng⁶, Peng Xiao⁷

Affiliations

¹ 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.
² Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
³ Department of Immunology, Harvard Medical School, Boston, 02120, USA.
⁴ 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.
⁵ Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
⁶ 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. Electronic address: d_fengwm@sina.com.
⁷ 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. Electronic address: tulipxp@zju.edu.cn.

Abstract

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.

Keywords: Butyrate; Colorectal cancer; Ferroptosis; c-Fos; xCT.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Butyrates / pharmacology
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Ferroptosis*
Mice
Oxaliplatin
Tumor Microenvironment

Substances

Butyrates
Oxaliplatin