{"doi":"10.1172/jci159940","title":"CRISPR/Cas9 screen uncovers functional translation of cryptic lncRNA-encoded open reading frames in human cancer","abstract":"Emerging evidence suggests that cryptic translation within long noncoding RNAs (lncRNAs) may produce novel proteins with important developmental/physiological functions. However, the role of this cryptic translation in complex diseases (e.g., cancer) remains elusive. Here, we applied an integrative strategy combining ribosome profiling and CRISPR/Cas9 screening with large-scale analysis of molecular/clinical data for breast cancer (BC) and identified estrogen receptor α-positive (ER+) BC dependency on the cryptic ORFs encoded by lncRNA genes that were upregulated in luminal tumors. We confirmed the in vivo tumor-promoting function of an unannotated protein, GATA3-interacting cryptic protein (GT3-INCP) encoded by LINC00992, the expression of which was associated with poor prognosis in luminal tumors. GTE-INCP was upregulated by estrogen/ER and regulated estrogen-dependent cell growth. Mechanistically, GT3-INCP interacted with GATA3, a master transcription factor key to mammary gland development/BC cell proliferation, and coregulated a gene expression program that involved many BC susceptibility/risk genes and impacted estrogen response/cell proliferation. GT3-INCP/GATA3 bound to common cis regulatory elements and upregulated the expression of the tumor-promoting and estrogen-regulated BC susceptibility/risk genes MYB and PDZK1. Our study indicates that cryptic lncRNA-encoded proteins can be an important integrated component of the master transcriptional regulatory network driving aberrant transcription in cancer, and suggests that the \"hidden\" lncRNA-encoded proteome might be a new space for therapeutic target discovery.","journal":"Journal of Clinical Investigation","year":2023,"id":320953,"datarank":0.5775221402565088,"base_score":3.8501476017100584,"endowment":3.8501476017100584,"self_citation_contribution":0.5775221402565088,"citation_network_contribution":0.0,"self_endowment_contribution":0.5775221402565088,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":46,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":446093,"name":"Yanjun Wei","orcid":"0000-0003-4200-2859","position":1,"is_corresponding":false},{"id":307312,"name":"Peng Zhang","orcid":"0000-0001-9303-1639","position":2,"is_corresponding":false},{"id":345631,"name":"Longyong Xu","orcid":"0000-0002-8574-4062","position":3,"is_corresponding":false},{"id":1032359,"name":"Zhenzhen Zhang","orcid":"0000-0001-5572-6202","position":4,"is_corresponding":false},{"id":1018811,"name":"Kangyu Lin","orcid":"0000-0003-0140-2557","position":5,"is_corresponding":false},{"id":666245,"name":"Jiakai Hou","orcid":"0000-0003-2875-8756","position":6,"is_corresponding":false},{"id":691198,"name":"Xiangdong Lv","orcid":"0000-0001-5310-5816","position":7,"is_corresponding":false},{"id":345632,"name":"Yao Ding","orcid":"0000-0002-0559-5846","position":8,"is_corresponding":false},{"id":396322,"name":"Yulun Chiu","orcid":null,"position":9,"is_corresponding":false},{"id":255488,"name":"Antrix Jain","orcid":"0000-0002-2815-3645","position":10,"is_corresponding":false},{"id":1032360,"name":"Nelufa Islam","orcid":"0000-0002-9487-4635","position":11,"is_corresponding":false},{"id":57598,"name":"Anna Malovannaya","orcid":"0000-0003-2953-6485","position":12,"is_corresponding":false},{"id":107252,"name":"Yun Wu","orcid":"0000-0002-4071-8151","position":13,"is_corresponding":false},{"id":530001,"name":"Feng Ding","orcid":"0000-0003-0879-854X","position":14,"is_corresponding":false},{"id":86426,"name":"Han Xu","orcid":"0000-0002-8654-461X","position":15,"is_corresponding":false},{"id":341318,"name":"Ming Sun","orcid":"0000-0002-1173-2288","position":16,"is_corresponding":false},{"id":256052,"name":"Xi Chen","orcid":"0000-0002-7995-6202","position":17,"is_corresponding":false},{"id":281250,"name":"Yiwen Chen","orcid":"0000-0002-7706-7540","position":18,"is_corresponding":false},{"id":694909,"name":"Caishang Zheng","orcid":"0000-0001-5636-3642","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:07:27.434133Z","pmid":"36856111","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":[]}