Cell Death and Disease (Dec 2024)
Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis
- Zengzhuang Yuan,
- Xinyan Han,
- Manyu Xiao,
- Taoyu Zhu,
- Yaping Xu,
- Qian Tang,
- Chen Lian,
- Zijin Wang,
- Junming Li,
- Boyu Wang,
- Changhui Li,
- Xiaochen Xiang,
- Ruobai Jin,
- Yufei Liu,
- Xinyu Yu,
- Kehang Zhang,
- Songsong Li,
- Madhumita Ray,
- Rong Li,
- Artiom Gruzdev,
- Shiqun Shao,
- Fangwei Shao,
- Hua Wang,
- Wang Lian,
- Yong Tang,
- Di Chen,
- Ying Lei,
- Xuru Jin,
- Qinglin Li,
- Weiwen Long,
- Huaqiong Huang,
- Francesco J. DeMayo,
- Jian Liu
Affiliations
- Zengzhuang Yuan
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Xinyan Han
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Manyu Xiao
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Taoyu Zhu
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Yaping Xu
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Qian Tang
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Chen Lian
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Zijin Wang
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Junming Li
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Boyu Wang
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Changhui Li
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Xiaochen Xiang
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Ruobai Jin
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Yufei Liu
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Xinyu Yu
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Kehang Zhang
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Songsong Li
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Madhumita Ray
- Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS)
- Rong Li
- Department of Obstetrics, Gynecology and Women’ Health, University of Missouri
- Artiom Gruzdev
- Gene Editing and Mouse Model Core, National Institute of Environmental Health Sciences (NIEHS)
- Shiqun Shao
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University
- Fangwei Shao
- Zhejiang University-University of Illinois Urbana-Champaign Institute, Zhejiang University
- Hua Wang
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign
- Wang Lian
- Department of Thoracic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University
- Yong Tang
- Department of Thoracic Surgery, Shenzhen Nanshan People’s Hospital
- Di Chen
- Center for Regeneration and Cell Therapy of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- Ying Lei
- Department of Respiratory and Critical Care Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical Hospital, Quzhou People’s Hospital
- Xuru Jin
- Department of Respiratory and Critical Care Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical Hospital, Quzhou People’s Hospital
- Qinglin Li
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital
- Weiwen Long
- Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University
- Huaqiong Huang
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine
- Francesco J. DeMayo
- Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS)
- Jian Liu
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University
- DOI
- https://doi.org/10.1038/s41419-024-07274-5
- Journal volume & issue
-
Vol. 15,
no. 12
pp. 1 – 14
Abstract
Abstract Ferroptosis has been shown to play a crucial role in preventing cancer development, but the underlying mechanisms of dysregulated genes and genetic alternations driving cancer development by regulating ferroptosis remain unclear. Here, we showed that the synergistic role of ELF3 overexpression and PTEN deficiency in driving lung cancer development was highly dependent on the regulation of ferroptosis. Human ELF3 (hELF3) overexpression in murine lung epithelial cells only caused hyperplasia with increased proliferation and ferroptosis. hELF3 overexpression and Pten genetic disruption significantly induced lung tumor development with increased proliferation and inhibited ferroptosis. Mechanistically, we found it was due to the induction of SCL7A11, a typical ferroptosis inhibitor, and ELF3 directly and positively regulated SCL7A11 in the PTEN-deficient background. Erastin-mediated inhibition of SCL7A11 induced ferroptosis in cells with ELF3 overexpression and PTEN deficiency and thus inhibited cell colony formation and tumor development. Clinically, human lung tumors showed a negative correlation between ELF3 and PTEN expression and a positive correlation between ELF3 and SCL7A11 in a subset of human lung tumors with PTEN-low expression. ELF3 and SCL7A11 expression levels were negatively associated with lung cancer patients’ survival rates. In summary, ferroptosis induction can effectively attenuate lung tumor development induced by ELF3 overexpression and PTEN downregulation or loss-of-function mutations.
