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The induction of ferroptosis by KLF11/NCOA4 axis: the inhibitory role in clear cell renal cell carcinoma

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Abstract

Ferroptosis is a form of cell death and has great potential application in the treatment of many cancers, including clear cell renal cell carcinoma (ccRCC). Herein, we identified the essential roles of Krüppel-like factor 11 (KLF11) in suppressing the progression of ccRCC. By analyzing mRNA expression data from the Gene Expression Omnibus (GEO) database, we found that KLF11 was a significantly downregulated gene in ccRCC tissues. The results of subsequent functional assays verified that KLF11 played an antiproliferative role in ccRCC cells and xenograft tumors. Furthermore, gene set enrichment analysis indicated that ferroptosis was involved in ccRCC development, and correlation analysis revealed that KLF11 was positively related to ferroptosis drivers. We also found that KLF11 promoted ferroptosis in ccRCC by downregulating the protein expression of ferritin, system xc (−) cystine/glutamate antiporter (xCT), and glutathione peroxidase 4 (GPX4), acting as the inhibitory factors of ferroptosis and increasing the intracellular levels of lipid reactive oxygen species (ROS). As a transcriptional regulator, KLF11 significantly increased the promoter activity of nuclear receptor coactivator 4 (NCOA4), a gene significantly downregulated in ccRCC and whose low expression is associated with poor survival. The characteristics of ccRCC cells caused by KLF11 overexpression were reversed after NCOA4 silencing. In summary, the present study suggests that KLF11 suppresses the progression of ccRCC by increasing NCOA4 transcription. Therefore, the KLF11/NCOA4 axis may serve as a novel therapeutic target for human ccRCC.

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Authors and Affiliations

  1. Department of Urology,, Cancer Hospital of China Medical University (Liaoning Cancer Hospital and Institute), No. 44, Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, China

    Zi-Qi Zhou, Xi Lv, Shi-Bo Liu, Hong-Chen Qu, Qing-Peng Xie & Gang Li

  2. Department of Geriatric Cardiology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning Province, China

    Long-Feng Sun

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Contributions

ZQZ, LFS, and GL designed and supervised the study. ZQZ, XL, and SBL conducted the experiments. The data were collected and analyzed by ZQZ, HCQ, and QPX. The manuscript was written by ZQZ and edited by LFS and GL. All the authors read and approved the final manuscript and author contribution statements.

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Correspondence to Long-Feng Sun or Gang Li.

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The authors declare that they have no competing interests.

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All animal experiments were approved by the Animal Ethical and Welfare Committee of Liaoning Cancer Hospital & Institute and conducted in compliance with the guidelines for the care and use of laboratory animals formulated by the Institutional Animal Care and Use Committee of China.

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13577_2023_973_MOESM1_ESM.tif

Supplementary file1 Fig. 1 Identification and GO functional annotation of DEGs between ccRCC tissues and normal kidney tissues. (A) A volcano plot of genes in GSE100666, with criteria of |log2FC|> 1 and p < 0.05 applied to identify DEGs. (B) GO analysis of DEGs in the categories of BP, CC, and MF. The inner ring was a bar plot where the bar height indicated the significance of the term and the color indicated the z score. The outer ring displayed scatterplots of the expression levels (log2FC) for the genes in each term (TIF 1646 KB)

13577_2023_973_MOESM2_ESM.tif

Supplementary file2 Fig. 2 KEGG pathway enrichment analysis in ccRCC tissues. (A) The ranking plot of ten enriched KEGG pathways was arranged according to the net enrichment score (TIF 924 KB)

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Zhou, ZQ., Lv, X., Liu, SB. et al. The induction of ferroptosis by KLF11/NCOA4 axis: the inhibitory role in clear cell renal cell carcinoma. Human Cell 36, 2162–2178 (2023). https://doi.org/10.1007/s13577-023-00973-9

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