Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis

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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Journal
Cell Death and Disease
Published
2024-12-18
DOI
https://doi.org/10.1038/s41419-024-07274-5
Citations
3
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
1.26

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article

Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis

Tian-Wang Zhu, Manyu Xiao, Rong Jin, Fangwei Shao et al.
3 citations
Cell Death and Disease
Ferroptosis and cancer prognosis
1.26
article

Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis

Tian-Wang Zhu, Manyu Xiao, Rong Jin, Fangwei Shao, Artiom Gruzdev, Xiaochen Xiang, Xinyu Yu, Kehang Zhang, Zijin Wang, Shiqun Shao, Boyu Wang, Weiwen Long, Madhumita Ray, Changhui Li, Francesco J. DeMayo, Junming Li, Di Chen, Yufei Liu, Rong Li, Hua Wang, Lian Chen, Jian Liu, Lian Wang, Songsong Li, Qinglin Li, Ying Jie Lei, Qian� Tang, Huaqiong Huang, Yaping Xu, Yong Tang, Xuru Jin, Zengzhuang Yuan, Xinyan Han
article en
3 citations

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.

Cell Death and DiseaseVol. 15(12)
University of Illinois Urbana-Champaign (US), Wright State University (US), Wenzhou Medical University (CN), University of Missouri Health System (US), First Affiliated Hospital of Wenzhou Medical University (CN), Edinburgh College (GB), Institute for Stem Cell Biology and Regenerative Medicine (IN), Quzhou City People's Hospital (CN), National Institute of Environmental Health Sciences (US), Zhejiang Cancer Hospital (CN), Zhejiang Yongning Pharma (China) (CN), ShenZhen People’s Hospital (CN), Zhejiang Lab (CN), Second Affiliated Hospital of Zhejiang University (CN), Zhejiang University-University of Edinburgh Institute (CN), Zhejiang University (CN), University of Missouri (US), University of Edinburgh (GB)
National Science Foundation, Wenzhou Medical University, Zhejiang University, National Science and Technology Major Project, National Institutes of Health, University of Illinois at Urbana-Champaign, Wu Jieping Medical Foundation, National Institute of Environmental Health Sciences
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Openalex Percentile: Top 18%
Ferroptosis and cancer prognosis
1.26
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