{"doi":"10.1101/2021.01.09.425982","title":"Dependency of LKB1-inactivated lung cancer on aberrant CRTC-CREB activation","abstract":"Abstract Lung cancer with loss-of-function of the LKB1 tumor suppressor is a common aggressive subgroup with no effective therapies. LKB1- deficiency induces constitutive activation of cAMP/CREB-mediated transcription by a family of three CREB-regulated transcription coactivators (CRTC1-3). However, the significance and mechanism of CRTC activation in promoting the aggressive phenotype of LKB1-null cancer remain poorly characterized. Here we observed overlapping CRTC expression patterns and mild growth phenotypes of individual CRTC-knockouts in lung cancer, suggesting functional redundancy of CRTC1-3. We consequently designed a dominant-negative mutant (dnCRTC) to block all three CRTCs to bind and co-activate CREB. Expression of dnCRTC efficiently inhibited the aberrantly activated cAMP/CREB-mediated oncogenic transcriptional program induced by LKB1-deficiency, and specifically blocked the growth of LKB1-inactivated lung cancer. Collectively, this study provides direct proof for an essential role of the CRTC-CREB activation in promoting the malignant phenotypes of LKB1-null lung cancer and proposes the CRTC-CREB interaction interface as a novel therapeutic target.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":222910,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":650877,"name":"Jennifer W. Li","orcid":null,"position":1,"is_corresponding":false},{"id":650356,"name":"Zirong Chen","orcid":"0000-0002-0267-563X","position":2,"is_corresponding":false},{"id":650357,"name":"Wei Ni","orcid":"0000-0002-5729-827X","position":3,"is_corresponding":false},{"id":824122,"name":"Xuehui Li","orcid":"0000-0002-7495-2675","position":4,"is_corresponding":false},{"id":706883,"name":"Rongqiang Yang","orcid":null,"position":5,"is_corresponding":false},{"id":824123,"name":"Huangxuan Shen","orcid":"0000-0002-6552-9541","position":6,"is_corresponding":false},{"id":294615,"name":"Jian Liu","orcid":"0000-0002-1447-0973","position":7,"is_corresponding":false},{"id":239870,"name":"Francesco J. DeMayo","orcid":"0000-0002-9480-7336","position":8,"is_corresponding":false},{"id":98168,"name":"Jianrong Lu","orcid":"0000-0002-4969-6040","position":9,"is_corresponding":false},{"id":35279,"name":"Frederic J. Kaye","orcid":"0000-0001-8565-1854","position":10,"is_corresponding":false},{"id":415526,"name":"Lizi Wu","orcid":"0000-0002-0076-2617","position":11,"is_corresponding":false},{"id":650358,"name":"Xin Zhou","orcid":"0000-0002-0480-3068","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:54:07.287704Z","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":[]}