{"doi":"10.1002/ctm2.985","title":"UBQLN4 promotes STING proteasomal degradation during cisplatin‐induced DNA damage in triple‐negative breast cancer","abstract":"To the Editor: Cisplatin is a platinum agent that causes DNA damage and it is used as a single agent or in combination for the treatment of recurrent/unresectable triple-negative breast cancer (TNBC).1 There is a renewed interest in cisplatin usage to treat TNBC in neoadjuvant/metastatic settings.2 Treatment options become limited when patients develop resistance, thus new insights into the molecular mechanisms driving cisplatin resistance will improve TNBC patient outcomes. The aim of this study is to unravel novel molecular mechanisms controlling STING protein levels during cisplatin treatment. We hypothesised that during cisplatin-induced DNA damage, STING is recognised by UBQLN4, and degraded through the ubiquitin-proteasome system. UBQLN4 mRNA expression was analysed in the TCGA BRCA and GTEx datasets. UBQLN4 levels were significantly higher in primary TNBC tumours (Figure 1A,B). Patients with high UBQLN4 mRNA levels had significantly reduced relapse-free survival (RFS) (Figure 1C). UBQLN4 gene is in the 1q22 region, and the amplification of the 1q arm is a frequent event in breast cancer (BC) and other solid tumours.3, 4 UBQLN4 copy number variation (CNV) and mRNA levels showed a significant positive correlation in TNBC tumours and cell lines (Figure 1D,E). Immunohistochemistry analysis demonstrated significant elevated UBQLN4 protein levels for TNBC tumours (Figure 1F,G and Figure S1A). We have previously reported that UBQLN4 levels affect cisplatin sensitivity.5, 6 UBQLN4 levels were associated with increased cisplatin resistance in TNBC cell lines (Figure 1H). UBQLN4 depletion did not induce significant transcriptional changes in TNBC cell lines (Figure S1B–F) or reduce cellular proliferation (Figure S1G-J); however, it increased the sensitivity to cisplatin, whereas UBQLN4-OV led to cisplatin resistance (Figure 1I–K). In summary, the UBQLN4 gene amplification correlates with increased UBQLN4 levels that led to cisplatin resistance in TNBC cell lines. UBQLN4 interacts with the chaperone protein BAT3 to reduce proteotoxic cell stress by translocating misassembled ER-localised proteins for proteasomal degradation.7 BAT3 mRNA levels were significantly higher in primary TNBC tumours (Figure 1L,M), but high BAT3 mRNA levels did not associate with RFS (Figure S2A). BAT3 knockdown did not affect UBQLN4 levels or cellular proliferation (Figure S2B–E), but increased the sensitivity to cisplatin (Figure 1N,O). Cisplatin treatment significantly increased γ-H2AX foci-formation in UBQLN4-KO and BAT3-knockdown, but not in UBQLN4-OV cell lines (Figure S3A,B). Ubiquitination of BAT3-captured proteins is required for efficient protein degradation.8 Under cisplatin treatment and proteasomal degradation blockage, BAT3 co-immunoprecipitated with UBQLN4 in UBQLN4-OV and parental cell lines (Figure S3C,D,F,G). Under the same conditions, UBQLN4 and BAT3 co-immunoprecipitated with ubiquitinated DDK-tagged proteins (Figure S3E). These results suggested that UBQLN4 and BAT3 interact with specific ubiquitinated proteins during cisplatin treatment in TNBC cell lines. STING ubiquitination is required to initiate cytosolic DNA-mediated activation.9, 10 Therefore, we hypothesised that in response to cisplatin-induced DNA damage, STING is activated, ubiquitinated and regulated by UBQLN4-mediated proteasomal degradation. STING mRNA levels were significantly lower in primary TNBC tumours (Figure 2A,B). Patients with low STING mRNA levels had significantly poor RFS (Figure 2C). Increased phosphorylated TBK1 levels were observed after cisplatin treatment, suggesting the STING pathway activation (Figure 2D). STING protein levels showed a significant positive correlation with cisplatin response (Figure 2E). STING-knockdown did not affect UBQLN4/BAT3 levels or cellular proliferation (Figure S4A–C), but increased cisplatin resistance (Figure 2F,G). In conclusion, STING downregulation led to cisplatin resistance in TNBC cell lines. UBQLN4 and STING protein l","journal":"Clinical and Translational Medicine","year":2022,"id":270276,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":934033,"name":"Takamichi Yokoe","orcid":"0000-0001-7068-7117","position":1,"is_corresponding":false},{"id":934034,"name":"Yuta Kobayashi","orcid":"0000-0002-2029-8292","position":2,"is_corresponding":false},{"id":934541,"name":"Tomohiro Murakami","orcid":null,"position":3,"is_corresponding":false},{"id":934542,"name":"Peter J. Bostick","orcid":null,"position":4,"is_corresponding":false},{"id":934035,"name":"Yosef Shiloh","orcid":"0000-0002-1538-6060","position":5,"is_corresponding":false},{"id":70204,"name":"Dave S.�B. Hoon","orcid":"0000-0003-1915-3683","position":6,"is_corresponding":false},{"id":488315,"name":"Matías A. Bustos","orcid":"0000-0001-9625-1127","position":7,"is_corresponding":false},{"id":934032,"name":"Yoshiaki Shoji","orcid":"0000-0003-3074-1398","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-19T00:27:26.772098Z","pmid":"35839317","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":[]}