Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma

Abstract

Objective Aberrant epigenetic remodeling represents a molecular hallmark in lung adenocarcinoma (LUAD). We aim to investigate the biological roles of SETDB2 and its underlying associations with oxidative stress, providing therapeutic targets for individualized treatment of LUAD. Methods Differential analysis was conducted via Limma package, and Kaplan–Meier analysis was performed with survival package. CCK‐8, cell proliferation assay, transwell assay, and in vivo assays were conducted to assess the function of SETDB2. Western blot assay, RT‐qPCR, and immunohistochemistry (IHC) were conducted to assess the expression levels of SETDB2/NRF2. Chromatin immunoprecipitation (ChIP) assay and ChIP‐qPCR were conducted to assess the epigenetic roles of SETDB2. Results We found that SETDB2 expression is decreased in tumor samples versus normal tissues in TCGA‐LUAD cohort, LUAD‐EAS cohort, GSE72094 dataset, and independent Soochow‐LUAD dataset. Patients with low SETDB2 levels had a worse prognosis relative to those with high SETDB2. SETDB2 inhibition could significantly promote cell growth, migration ability, and stemness maintenance. Gene set enrichment analysis (GSEA) suggested that SETDB2 correlated with oxidative stress crosstalk and regulated NRF2 mRNA levels. ChIP assay suggested that SETDB2 mainly recruited the H3K9me3 enrichment at the NRF2 promoter region to suppress the mRNA levels of NRF2. Downregulated SETDB2 could activate NRF2 transcription and expression, thereby promoting its downstream targets, like NQO1, FTH1, and ME1. Functional experiments demonstrated that low SETDB2 allowed NRF2 to drive malignant processes of LUAD. SETDB2 overexpression attenuated the ability of NRF2 signaling to neutralize cellular reactive oxygen species (ROS) levels, leading to enhanced cell apoptosis. Overexpressed SETDB2 could inhibit tumor progression in vivo and further render LUAD cells sensitive to chemotherapy. Conclusions In conclusion, these findings uncovered the suppressive role of SETDB2 in LUAD. SETDB2 negatively regulates NRF2 signaling to modulate tumor progression, which creates a therapeutic vulnerability in LUAD.

An antioxidant feedforward cycle coordinated by linker histone variant H1.2 and NRF2 that drives nonsmall cell lung cancer progression

“…Usually, cytoplasmic NRF2 binds to Kelch-like ECH-associated protein-1 (KEAP1) and undergoes KEAP1-mediated degradation; upon oxidative stress, NRF2 disassociates from KEAP1, translocates to nucleus, and activates transcription through binding to the antioxidant response element (ARE) sequences within the promoters of detoxifying and antioxidant genes ( 13 ). Recent studies suggested that oxidative stress can be influenced by the status of histones, a family of proteins that organize DNA into chromatin and widely involved in gene transcription ( 15 – 18 ). For example, NRF2 recruits histone acetyltransferases to cooperatively activate transcription ( 17 ); upregulation of trimethylated histone H3K9 (H3K9me3) suppresses NRF2 transcription and consequently increases cellular oxidative stress ( 18 ).…”

“…Recent studies suggested that oxidative stress can be influenced by the status of histones, a family of proteins that organize DNA into chromatin and widely involved in gene transcription ( 15 – 18 ). For example, NRF2 recruits histone acetyltransferases to cooperatively activate transcription ( 17 ); upregulation of trimethylated histone H3K9 (H3K9me3) suppresses NRF2 transcription and consequently increases cellular oxidative stress ( 18 ). However, whether NRF2 regulates histone remains unknown.…”