{"doi":"10.3389/fimmu.2024.1430187","title":"TGF-β and TNF-α interaction promotes the expression of MMP-9 through H3K36 dimethylation: implications in breast cancer metastasis","abstract":"Increased MMP-9 expression in the tumor microenvironment (TME) plays a crucial role in the extracellular matrix remodeling to facilitate cancer invasion and metastasis. However, the mechanism of MMP-9 upregulation in TME remains elusive. Since TGF-β and TNF-α levels are elevated in TME, we asked whether these two agents interacted to induce/augment MMP-9 expression. Using a well-established MDA-MB-231 breast cancer model, we found that the synergy between TGF-β and TNF-α led to MMP-9 upregulation at the transcriptional and translational levels, compared to treatments with each agent alone. Our in vitro findings are corroborated by co-expression of elevated MMP-9 with TGF-β and TNF-α in human breast cancer tissues. Mechanistically, we found that the MMP-9 upregulation driven by TGF-β/TNF-α cooperativity was attenuated by selective inhibition of the TGF-βRI/Smad3 pathway. Comparable outcomes were observed upon inhibition of TGF-β-induced phosphorylation of Smad2/3 and p38. As expected, the cells defective in Smad2/3 or p38-mediated signaling did not exhibit this synergistic induction of MMP-9. Importantly, the inhibition of histone methylation but not acetylation dampened the synergistic MMP-9 expression. Histone modification profiling further identified the H3K36me2 as an epigenetic regulatory mark of this synergy. Moreover, TGF-β/TNF-α co-stimulation led to increased levels of the transcriptionally permissive dimethylation mark at H3K36 in the MMP-9 promoter. Comparable outcomes were noted in cells deficient in NSD2 histone methyltransferase. In conclusion, our findings support a cooperativity model in which TGF-β could amplify the TNF-α-mediated MMP-9 production via chromatin remodeling and facilitate breast cancer invasion and metastasis.","journal":"Frontiers in Immunology","year":2024,"id":422363,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1216054,"name":"Amnah Al-Sayyar","orcid":"0000-0002-6854-0746","position":1,"is_corresponding":false},{"id":1046527,"name":"Texy Jacob","orcid":"0000-0002-1413-9535","position":2,"is_corresponding":false},{"id":1216055,"name":"Fatemah Bahman","orcid":"0000-0003-3291-802X","position":3,"is_corresponding":false},{"id":1216680,"name":"Nadeem Akhter","orcid":null,"position":4,"is_corresponding":false},{"id":1216681,"name":"Ajit Wilson","orcid":null,"position":5,"is_corresponding":false},{"id":682137,"name":"Sardar Sindhu","orcid":"0000-0001-9936-1575","position":6,"is_corresponding":false},{"id":271166,"name":"Yusuf A. Hannun","orcid":"0000-0003-3349-3369","position":7,"is_corresponding":false},{"id":316844,"name":"Rasheed Ahmad","orcid":"0000-0001-5746-0743","position":8,"is_corresponding":false},{"id":104495,"name":"Fahd Al‐Mulla","orcid":"0000-0001-5409-3829","position":9,"is_corresponding":false},{"id":638031,"name":"Shihab Kochumon","orcid":"0009-0000-2061-5895","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T01:57:46.393290Z","pmid":"39351229","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}