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<p>M1 macrophage exosomes (M1-Exos) have been shown to play a significant role in regulating Lung adenocarcinoma (LUAD) progression. Krüppel-Like Factor 6 (KLF6) is a widely expressed nuclear transcriptional regulator involving in various key cellular processes and functions as a tumor suppressor. Here, this study aimed to investigate the role of KLF6 in LUAD and whether M1-Exos function in LUAD by KLF6.&#xa0;Levels of mRNA and protein were detected using qRT-PCR and western blotting. Exosomes were isolated from M1 macrophages and co-cultured with LUAD cell lines for functional analysis. In vitro analyses were conducted using 5-ethynyl-2’-deoxyuridine assay, flow cytometry and transwell assay. The N6-methyladenosine (m6A) modification profile was analyzed using the methylated RNA immunoprecipitation assay and the interaction was determined by RNA Immunoprecipitation assay. The murine model was established for in vivo analysis.&#xa0;M1 macrophage exosomes suppressed LUAD cell proliferation, migration and invasion. Further analyses showed that KLF6 was packaged in M1 macrophage exosomes and could be transferred into LUAD cells. Functionally, the incubation of KLF6-decreased M1 macrophage exosomes led to the enhancement of LUAD cell proliferation, migration and invasion. Mechanistically, alkylation repair homolog protein 5 (ALKBH5), an RNA m6A demethylase, could reduce KLF6 m6A modification and then broke the stabilization of KLF6&#xa0;and decreased its expression in M1 macrophages and LUAD cells. Importantly, ALKBH5 reversed the anticancer effects of M1-Exo on LUAD cells. Moreover, the inhibition of LUAD tumor growth in vivo mediated by M1-Exo was also impeded by ALKBH5.&#xa0;In conclusion,&#xa0;M1 macrophage exosomes inhibited LUAD growth by reducing ALKBH5-mediated KLF6 demethylation.</p> Graphical Abstract <p>Decreased ALKBH5 causes the increase of KLF6 expression in M1 macrophages by reducing KLF6 demethylation, KLF6 is packaged in M1 macrophage exosomes and can be transferred into LUAD cells via exosomes, so as to suppress LUAD cell growth, migration and invasion.</p> <p></p>

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M1 macrophage exosomes inhibit lung adenocarcinoma growth by up-regulating KLF6 via the reduction of ALKBH5-mediated KLF6 demethylation

  • 期刊论文

  • 发表日期：

    2025年12月5日

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  • Jian Gou,
  • Ting Jia,
  • Shasha Song,
  • Jie He,
  • Dan Zhao

摘要

M1 macrophage exosomes (M1-Exos) have been shown to play a significant role in regulating Lung adenocarcinoma (LUAD) progression. Krüppel-Like Factor 6 (KLF6) is a widely expressed nuclear transcriptional regulator involving in various key cellular processes and functions as a tumor suppressor. Here, this study aimed to investigate the role of KLF6 in LUAD and whether M1-Exos function in LUAD by KLF6. Levels of mRNA and protein were detected using qRT-PCR and western blotting. Exosomes were isolated from M1 macrophages and co-cultured with LUAD cell lines for functional analysis. In vitro analyses were conducted using 5-ethynyl-2’-deoxyuridine assay, flow cytometry and transwell assay. The N6-methyladenosine (m6A) modification profile was analyzed using the methylated RNA immunoprecipitation assay and the interaction was determined by RNA Immunoprecipitation assay. The murine model was established for in vivo analysis. M1 macrophage exosomes suppressed LUAD cell proliferation, migration and invasion. Further analyses showed that KLF6 was packaged in M1 macrophage exosomes and could be transferred into LUAD cells. Functionally, the incubation of KLF6-decreased M1 macrophage exosomes led to the enhancement of LUAD cell proliferation, migration and invasion. Mechanistically, alkylation repair homolog protein 5 (ALKBH5), an RNA m6A demethylase, could reduce KLF6 m6A modification and then broke the stabilization of KLF6 and decreased its expression in M1 macrophages and LUAD cells. Importantly, ALKBH5 reversed the anticancer effects of M1-Exo on LUAD cells. Moreover, the inhibition of LUAD tumor growth in vivo mediated by M1-Exo was also impeded by ALKBH5. In conclusion, M1 macrophage exosomes inhibited LUAD growth by reducing ALKBH5-mediated KLF6 demethylation.

Graphical Abstract

Decreased ALKBH5 causes the increase of KLF6 expression in M1 macrophages by reducing KLF6 demethylation, KLF6 is packaged in M1 macrophage exosomes and can be transferred into LUAD cells via exosomes, so as to suppress LUAD cell growth, migration and invasion.