ETS homologous factor, controlled by lysine-specific demethylase 5B, suppresses clear cell renal cell carcinoma by inducing Filamin-B

• Published in: Gene Vol. 927; p. 148702
• Main Authors: Wang, Fang, Huang, Jiangbo, Zeng, Shun, Pan, Ying, Zhou, Hao
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.11.2024
• Subjects: Clear cell renal cell carcinoma; EHF; FLNB; Immune evasion; KDM5B; KDM5B; EHF; FITC; CCK-8; PI; FLNB; Clear cell renal cell carcinoma; Immune evasion; CcRCC; ChIP
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2024.148702

•Tumor suppressor EHF is significantly reduced in ccRCC cells.•EHF inhibits the biological behavior of ccRCC cells and tumor growth in vivo.•EHF activates FLNB transcription, and FLNB silencing promotes ccRCC progression.•Expression of EHF and FLNB is strongly associated with macrophage M2 polarization.•KDM5B inhibits EHF by H3K4me3 demethylation and plays oncogenic role in ccRCC. Clear cell renal cell carcinoma (ccRCC) remains a deadly disease with a poor prognosis. Here, we identified the ETS homologous factor (EHF) and its target Filamin-B (FLNB) as molecules related to immune evasion in ccRCC. We also explored the upstream modifier that manipulates EHF in ccRCC. Cell proliferation and apoptosis assay, wound healing assay, and Transwell assay were designed to analyze the effects of EHF or FLNB knockdown on the biological activity of ccRCC cells. The growth of differently treated ccRCC cells was assessed by orthotopic tumors. ccRCC cells with different treatments were co-cultured with macrophages, and the role of the lysine-specific demethylase 5B (KDM5B)/EHF/FLNB axis on macrophage polarization or ccRCC progression was characterized by detecting the expression of M2 macrophage markers in the co-culture system or tumor tissues of tumor-bearing mice. The expression of EHF and FLNB was higher, while KDM5B was lower in HK2 cells than in ccRCC cells. EHF overexpression inhibited the biological behavior of ccRCC cells and tumor growth in mice. EHF activated FLNB transcription. Knockdown of FLNB supported the biological activity of ccRCC cells and tumor growth and reversed M2 macrophage polarization in tumor tissues of mice in the presence of EHF. KDM5B inhibited EHF expression by H3K4me3 demethylation, and EHF knockdown potentiated M2 macrophage polarization and tumor growth in vivo repressed by KDM5B knockdown. KDM5B inhibited the expression of EHF by repressing H3K4me3 modification and the transcription of FLNB by EHF to promote immune evasion and progression of ccRCC.