Targeting AKT induced Ferroptosis through FTO/YTHDF2-dependent GPX4 m6A methylation up-regulating and degradating in colorectal cancer

Ge Zhang; Wunan Mi; Chuyue Wang; Jiehan Li; Yizheng Zhang; Nannan Liu; Meimei Jiang; Guiyun Jia; Feng Wang; Ge Yang; Lingling Zhang; Jiangang Wang; Yang Fu; Yingjie Zhang

doi:10.1038/s41420-023-01746-x

Targeting AKT induced Ferroptosis through FTO/YTHDF2-dependent GPX4 m6A methylation up-regulating and degradating in colorectal cancer

Cell Death Discov. 2023 Dec 15;9(1):457. doi: 10.1038/s41420-023-01746-x.

Authors

Ge Zhang^#^{1

2

3}, Wunan Mi^#^{1

2

3

4}, Chuyue Wang³, Jiehan Li², Yizheng Zhang², Nannan Liu^{1

3}, Meimei Jiang^{1

3}, Guiyun Jia^{1

3}, Feng Wang⁵, Ge Yang⁶, Lingling Zhang⁷, Jiangang Wang⁸, Yang Fu⁹, Yingjie Zhang^{10

11

12}

Affiliations

¹ Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China.
² Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
³ School of Biomedical Sciences, Hunan University, Changsha, 410082, China.
⁴ Department of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁵ Department of Gastroenterology, The Tenth People's Hospital of Shanghai, Tongji University, Shanghai, 200072, China.
⁶ Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
⁷ Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
⁸ Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China. 600410@csu.edu.cn.
⁹ Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. fuyang@zzu.edu.cn.
¹⁰ Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China. yingjiezhang@hnu.edu.cn.
¹¹ School of Biomedical Sciences, Hunan University, Changsha, 410082, China. yingjiezhang@hnu.edu.cn.
¹² Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, PR China. yingjiezhang@hnu.edu.cn.

^# Contributed equally.

Abstract

Ferroptosis is a new type of iron-dependent programmed cell death induced by lipid peroxidation. However, the underlying mechanisms and function in tumor therapy still remain undisclosed especially in post-transcription regulation. Here, we found that targeting AKT significantly induced GPX4 dependent ferroptosis and suppressed colorectal cancer growth both in vitro and in vivo. During this process, demethylase FTO was downregulated, which increased the m6A methylation level of GPX4, subsequently recognized by YTHDF2 and degraded. Prediction results showed that there are three potential methylated sites (193/647/766), and 193 site was identified as the right one, which was demethylated by FTO and read by YTHDF2. In parallel, AKT inhibition caused the accumulation of ROS which had a negative feedback on GPX4 expression. In addition, protective autophagy was initiated by MK2206 stimulation, while blocking autophagy further increased ferroptosis and markedly enhanced the anti-tumor activity of MK2206. In a word, inhibiting AKT activated ferroptosis through FTO/YTHDF2/GPX4 axis to suppress colon cancer progression, which raised FTO/GPX4 as potential biomarkers and targets in colorectal cancer therapy.

Abstract

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