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

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:36504353", "kind": "science-record", "revision": 4, "content_hash": "sha256:1b5f2926d602b7a31f14bbd17197e44671ac69dc6ffe0f561976c9adcae52c59", "created_at": "2026-11-01T19:01:00Z", "updated_at": "2026-11-01T22:50:48Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma.", "doi": "10.1002/cam4.5451", "pmid": "36504353", "authors": ["Guangda Yuan", "Bowen Hu", "Jun Ma", "Chuanyu Zhang", "Hongya Xie", "Tengteng Wei", "Yong Yang", "Bin Ni"], "journal": "Cancer medicine", "year": 2023, "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.\nMETHODS: 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.\nRESULTS: 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.\nCONCLUSIONS: 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.", "claims": [{"id": "claim-method", "statement": "The differential analysis was conducted via Limma package. The Kaplan–Meier analysis was conducted via Survival package.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36504353", "locator": "sections[14] \"Bioinformatic methods\" paragraph 2", "quote": "The differential analysis was conducted via Limma package. The Kaplan–Meier analysis was conducted via Survival package."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The molecular experiment data generated and analyzed during the current study are available from the corresponding author on reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36504353", "locator": "sections[32] \"DATA AVAILABILITY STATEMENT\" paragraph 2", "quote": "The molecular experiment data generated and analyzed during the current study are available from the corresponding author on reasonable request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Lastly, we conducted the Kaplan–Meier analysis and found that patients with low SETDB2 mRNA levels had worse prognosis with lower overall survival (OS) rates than those with high SETDB2 mRNA levels (log‐rank test p < 0.0001) (Figure 1G).", "kind": "quantitative", "target": {"value": 0.0001, "unit": "p-value", "tolerance": null, "source": "Lastly, we conducted the Kaplan–Meier analysis and found that patients with low SETDB2 mRNA levels had worse prognosis with lower overall survival (OS) rates than those with high SETDB2 mRNA levels (log‐rank test p < 0.0001) (Figure 1G)."}, "evidence": [{"asset": "source:pmid:36504353", "locator": "sections[17] \"Bioinformatic analysis shows that SETDB2 expresses lowly in LUAD versus normal tissues and is a prognostic factor\" paragraph 2", "quote": "Lastly, we conducted the Kaplan–Meier analysis and found that patients with low SETDB2 mRNA levels had worse prognosis with lower overall survival (OS) rates than those with high SETDB2 mRNA levels (log‐rank test p < 0.0001) (Figure 1G)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Lastly, we conducted the Kaplan–Meier analysis and found that patients with low SETDB2 mRNA levels had worse prognosis with lower overall survival (OS) rates than those with high SETDB2 mRNA levels (log‐rank test p < 0.0001) (Figure 1G).", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:36504353"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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Overexpressed SETDB2 could inhibit tumor pr", "nalysis was performed with survival package. CCK-8, cell proliferation assay, transwell assay,"], "order_basis": "paper_text_order:512", "id": "assay:1"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ll proliferation assay, transwell assay, and in vivo assays were conducted to assess the function", "essed SETDB2 could inhibit tumor progression in vivo and further render LUAD cells sensitive to c", "and blinded for peer review. The BALB/c nude mice were purchased from SLAC Laboratory Animal Co., L", "ed from SLAC Laboratory Animal Co., Ltd. The mice were bred and maintained in mouse facilities. Aft"], "order_basis": "paper_text_order:566", "id": "assay:2"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["conducted to assess the function of SETDB2. Western blot assay, RT-qPCR, and immunohistochemistry (IH", "d this finding in our fresh LUAD samples via western blot, in which the protein levels of SETDB2 were", "nd paired normal lung epithelium tissues via western blot (N = 8). Supplementary Materials Figure S1."], "order_basis": "paper_text_order:631", "id": "assay:3"}, {"role": "data_generation", "definition_id": "qpcr", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["the function of SETDB2. Western blot assay, RT-qPCR, and immunohistochemistry (IHC) were conduct", "e function of SETDB2. Western blot assay, RT-qPCR, and immunohistochemistry (IHC) were conduct", "in immunoprecipitation (ChIP) assay and ChIP-qPCR were conducted to assess the epigenetic role"], "order_basis": "paper_text_order:651", "id": "assay:4"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["of SETDB2. Western blot assay, RT-qPCR, and immunohistochemistry (IHC) were conducted to assess the expressio", "ot assay, RT-qPCR, and immunohistochemistry (IHC) were conducted to assess the expression lev", "low‐grade samples or normal lung tissues via immunohistochemistry (IHC) staining method (Figure 2A,B). We also", "ormal lung tissues via immunohistochemistry (IHC) staining method (Figure 2A,B). We also demo"], "order_basis": "paper_text_order:664", "id": "assay:5"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["mid construction The lung cancer cell lines (A549, H1299, and H522) and 293 T cells were all o"], "order_basis": "paper_text_order:2617", "id": "assay:6"}, {"role": "analysis", "definition_id": "differential_expression", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["The differential analysis was conducted via Limma package. The Kaplan–Meier analysis was conducted via Survival package."], "order_basis": "consumes_earlier_output", "id": "assay:7"}]}