{"doi":"10.7554/elife.96445","title":"Super-enhancer-driven ZFP36L1 promotes PD-L1 expression in infiltrative gastric cancer","abstract":"<jats:p>\n                    Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial. In this study, we performed H3K27ac Cleavage Under Targets and Tagmentation (CUT&amp;Tag) sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry, and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, chromatin immunoprecipitation (ChIP)/RIP experiments, and in vivo functional assays. We demonstrated that ZFP36L1, driven by an SE, enhances IFN-γ-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3ʹ untranslated region (3ʹUTR) of\n                    <jats:italic>HDAC3</jats:italic>\n                    mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation. Collectively, our findings provide mechanistic insights into the role of the SPI1-ZFP36L1-HDAC3-PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.\n                  </jats:p>","journal":"eLife","year":2024,"id":622513,"datarank":0.3958585994422889,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.0,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":640063,"name":"Jie Liu","orcid":"0000-0003-3307-1975","position":1,"is_corresponding":false},{"id":504554,"name":"Jia Cheng","orcid":"0000-0002-9639-5187","position":2,"is_corresponding":false},{"id":1608481,"name":"Wangyu Cai","orcid":null,"position":3,"is_corresponding":false},{"id":355801,"name":"Wen Xie","orcid":"0000-0003-3967-155X","position":4,"is_corresponding":false},{"id":833113,"name":"Kang Wang","orcid":"0009-0007-8979-1345","position":5,"is_corresponding":false},{"id":1608482,"name":"Lingyun Lin","orcid":null,"position":6,"is_corresponding":false},{"id":1543674,"name":"Jingjing Hou","orcid":null,"position":7,"is_corresponding":false},{"id":1608483,"name":"Jianchun Cai","orcid":"0000-0001-6217-6165","position":8,"is_corresponding":false},{"id":1608484,"name":"Huiqin Zhuo","orcid":"0000-0001-8322-4197","position":9,"is_corresponding":false},{"id":1608478,"name":"Xujin Wei","orcid":"0000-0002-1527-6400","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Super-enhancer-driven ZFP36L1 promotes PD-L1 expression in infiltrative gastric cancer","abstract":"<jats:p>\n                    Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial. In this study, we performed H3K27ac Cleavage Under Targets and Tagmentation (CUT&amp;Tag) sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry, and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, chromatin immunoprecipitation (ChIP)/RIP experiments, and in vivo functional assays. We demonstrated that ZFP36L1, driven by an SE, enhances IFN-γ-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3ʹ untranslated region (3ʹUTR) of\n                    <jats:italic>HDAC3</jats:italic>\n                    mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation. Collectively, our findings provide mechanistic insights into the role of the SPI1-ZFP36L1-HDAC3-PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.\n                  </jats:p>","is_dataset_classified":null,"base_score":2.639057329615259,"endowment":2.639057329615259,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39373630","pmcid":null,"openalex_id":"https://openalex.org/W4401415824","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"No. 81871979","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"No. 82272894","title":null},{"funder_name":"Natural Science Foundation of Fujian Province","grant_id":"No. 2021J02056","title":null},{"funder_name":"Natural Science Foundation of Fujian Province","grant_id":"No. 2020CXB048","title":null},{"funder_name":"Natural Science Foundation of Fujian Province","grant_id":"2021D026","title":null},{"funder_name":"Natural Science Foundation of Fujian Province","grant_id":"No. 2023J011594","title":null}],"total_grants":6,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2025,"count":10},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://elifesciences.org/reviewed-preprints/96445.pdf","host_type":"journal"},{"url":"https://elifesciences.org/reviewed-preprints/96445.pdf","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/articles/96445/elife-96445-v1.pdf","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/articles/96445/elife-96445-v1.xml","host_type":"publisher"},{"url":"https://elifesciences.org/articles/96445","host_type":"publisher"},{"url":"https://doi.org/10.7554/elife.96445","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39373630","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11458174","host_type":"repository"},{"url":"https://doaj.org/article/d6670c410b30435aa705cc4810b95748","host_type":"repository"}],"fields_of_study":["RNA modifications and cancer","Cancer-related molecular mechanisms research","RNA Research and Splicing"],"mesh_terms":["Animals","Enhancer Elements, Genetic","Humans","Stomach Neoplasms","Gene Expression Regulation, Neoplastic","Cell Line, Tumor","Mice","Butyrate Response Factor 1","B7-H1 Antigen"],"keywords":["Biology","Transcription factor","Chromatin immunoprecipitation","Cancer immunotherapy","Immune system","Cancer research","Cell biology","Molecular biology","Gene expression","Immunotherapy","Immunology","Promoter","Gene","Genetics"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T19:54:43.141205Z","pmid":null,"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":[]}