SUFU suppresses ferroptosis sensitivity in breast cancer cells via Hippo/YAP pathway

Kun Fang; Sha Du; Dachuan Shen; Zhipeng Xiong; Ke Jiang; Dapeng Liang; Jianxin Wang; Huizhe Xu; Lulu Hu; Xingyue Zhai; Yuting Jiang; Zhiyu Xia; Chunrui Xie; Di Jin; Wei Cheng; Songshu Meng; Yifei Wang

doi:10.1016/j.isci.2022.104618

SUFU suppresses ferroptosis sensitivity in breast cancer cells via Hippo/YAP pathway

iScience. 2022 Jun 16;25(7):104618. doi: 10.1016/j.isci.2022.104618. eCollection 2022 Jul 15.

Authors

Kun Fang^{1

2}, Sha Du², Dachuan Shen³, Zhipeng Xiong², Ke Jiang⁴, Dapeng Liang², Jianxin Wang², Huizhe Xu⁵, Lulu Hu⁶, Xingyue Zhai², Yuting Jiang², Zhiyu Xia², Chunrui Xie², Di Jin², Wei Cheng², Songshu Meng², Yifei Wang¹

Affiliations

¹ Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China.
² Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, No. 9 West Section, South Lvshun Road, Dalian 116044, China.
³ Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China.
⁴ Center for Single-Cell Omics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁵ Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, China.
⁶ Department of Clinical Laboratory, Qingdao Municipal Hospital, Qingdao University, Qingdao 266000, China.

Abstract

Ferroptosis is a new kind of regulated cell death that is characterized by highly iron-dependent lipid peroxidation. Cancer cells differ in their sensitivity to ferroptosis. Here we showed that the Suppressor of fused homolog (SUFU), a critical component in Hedgehog signaling, regulates ferroptosis sensitivity of breast cancer cells. Ectopic SUFU expression suppressed, whereas depletion of SUFU enhanced the sensitivity of breast cancer cells to RSL3-triggered ferroptosis through deregulation of ACSL4. Moreover, SUFU depletion promoted the activation of Yes-associated protein (YAP), thereby increasing the expression of ACSL4. Mechanistically, SUFU is associated with LATS1. Deletion of a region comprising residues 174-385 in SUFU disrupted SUFU binding to LATS1, thus abrogating SUFU-mediated downregulation of the YAP-ACSL4 axis and sensitivity to ferroptosis. Noteworthy, we showed that vincristine downregulated SUFU, thus increasing breast cancer cell sensitivity to RSL3 in vitro and in vivo. Together, our findings uncover SUFU as a novel regulator in ferroptosis sensitivity.

Keywords: Cancer; Cell biology; Functional aspects of cell biology.