TY - JOUR
T1 - Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis
AU - Yuan, Zengzhuang
AU - Han, Xinyan
AU - Xiao, Manyu
AU - Zhu, Taoyu
AU - Xu, Yaping
AU - Tang, Qian
AU - Lian, Chen
AU - Wang, Zijin
AU - Li, Junming
AU - Wang, Boyu
AU - Li, Changhui
AU - Xiang, Xiaochen
AU - Jin, Ruobai
AU - Liu, Yufei
AU - Yu, Xinyu
AU - Zhang, Kehang
AU - Li, Songsong
AU - Ray, Madhumita
AU - Li, Rong
AU - Gruzdev, Artiom
AU - Shao, Shiqun
AU - Shao, Fangwei
AU - Wang, Hua
AU - Lian, Wang
AU - Tang, Yong
AU - Chen, Di
AU - Lei, Ying
AU - Jin, Xuru
AU - Li, Qinglin
AU - Long, Weiwen
AU - Huang, Huaqiong
AU - DeMayo, Francesco J.
AU - Liu, Jian
N1 - Thanks Pro. Francesco J. DeMayo, for the guidance and support on this manuscript. Thanks for the Knockout Mouse Core Laboratory and mouse core facility at NIEHS. Thanks to Linwood Koonce\u2019s great work in handling mice at NIHES. Thanks to Manas Ray from NIEHS for the generation of LOXP-STOP-LOXP-hELF3 mice. The results shown here are partly based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. This work was supported by Zhejiang University-University of Edinburgh Institute (ZJE) and the Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University. We also acknowledge the help of members in JL\u2019s lab. We thank the ZJE core facility, especially the ZJE mouse core facility, and the Biomed-X Laboratory of ZJE Institute, School of Medicine, Zhejiang University, for continuous support. We thank the support from Zhejiang Province Engineering Research Center for Endoscope Instruments and Technology Development, Department of Pulmonary and Critical Care Medicine, Quzhou People\u2019s Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou 324000, China.
This work was supported by grants to Jian Liu from the NSF of Zhejiang Province (Distinguished Young Scholars: LR22H160002), the Natural Science Foundation (NSF) of China (General Grant: 82172899 and 82472637), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0502900/ 2023ZD0502902 and 2023ZD0507500/2023ZD0507501), Dr. Li Dak Sum & Yip Yio Chin Development Fund for Regenerative Medicine, Zhejiang University, the Open Fund of Zhejiang Provincial Key Laboratory of Pulmonology, ZJE seed funding, ZJE 2024 International Campus Talent Special Funding Program, ZJE-UoE Joint Research Project, and Startup Funding of Tenure-track Assistant Professor of Zhejiang University. This work was supported in part by the Dynamic Research Enterprise for Multidisciplinary Engineering Sciences (DREMES) at Zhejiang University and the University of Illinois Urbana Champaign, funded by Zhejiang University (To Jian Liu). This work was also supported by the intramural research program of the National Institute of Environmental Health Sciences, NIH project nos. Z1AES103311 (F. DeMayo). This work was also supported by Competitive Research Project of Quzhou Science & Technology Bureau (2023k114) and National Clinical Key Specialty Internal Fund of Quzhou Hospital Affiliated of Wenzhou Medical University (Internal Research Project) (GJZK-02), and Wu JiePing Medical Foundation [320.6750.2021-02-135]. The work was led by Principal Supervisors Jian Liu.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41419-024-07274-5
DO - 10.1038/s41419-024-07274-5
M3 - Article
C2 - 39695109
AN - SCOPUS:85212405640
SN - 2041-4889
VL - 15
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 12
M1 - 897
ER -