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

Redox Biology (Sep 2023)

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.

Journal volume & issue: Vol. 65
p. 102822

Abstract

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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.

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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