{"doi":"10.1016/j.jbc.2025.111001","title":"Triglyceride lipase PNPLA2–independent suppression of c-MYC signaling by the metabolic coactivator ABHD5 in prostate cancer","abstract":"The MYC oncogene encodes a transcription factor that regulates cell growth, metabolism, and proliferation. Its dysregulation is a hallmark of many cancers, including prostate cancer. Elevated c-MYC expression promotes tumor progression and therapy resistance, yet c-MYC remains a challenging therapeutic target because of its intrinsically disordered structure and lack of enzymatic activity. Identifying upstream regulators of MYC activity may reveal new therapeutic strategies. α/β-Hydrolase domain-containing protein 5 (ABHD5) is best known as a coactivator of the triglyceride lipase PNPLA2, facilitating intracellular lipolysis. However, recent studies have suggested a tumor-suppressive role for ABHD5 in various cancers, including prostate cancer, though the molecular mechanisms remain unclear. Here, we identify ABHD5 as a suppressor of c-MYC-driven transcriptional programs in prostate cancer cells. Transcriptomic profiling in 22Rv1 cells revealed that ABHD5 overexpression downregulates MYC target genes and reduces c-MYC protein levels. In contrast, ABHD5 knockout increased c-MYC protein expression, enhanced cell proliferation, and markedly elevated colony-forming capacity. ABHD5 deficiency also conferred resistance to the pharmacological c-MYC inhibitor 10058-F4. Notably, PNPLA2 knockout failed to phenocopy these effects, indicating that the tumor-suppressive function of ABHD5 is independent of its canonical lipolytic role. Furthermore, ABHD5 overexpression continued to suppress c-MYC in PNPLA2-deficient cells, confirming a lipase-independent mechanism. These findings define a previously unrecognized role for ABHD5 as a negative regulator of c-MYC and highlight a novel, noncanonical pathway linking lipid metabolism regulators to oncogene control in prostate cancer.","journal":"Journal of Biological Chemistry","year":2025,"id":537413,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE151957"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1423222,"name":"Guohua Chen","orcid":"0000-0001-8686-5483","position":1,"is_corresponding":false},{"id":394894,"name":"Guoli Zhou","orcid":"0000-0002-4497-5366","position":2,"is_corresponding":false},{"id":329153,"name":"James G. Granneman","orcid":"0000-0001-7013-6630","position":3,"is_corresponding":false},{"id":1229262,"name":"Jian Wang","orcid":"0000-0003-4503-5058","position":4,"is_corresponding":false},{"id":1423684,"name":"Aaron Lotvola","orcid":null,"position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T02:52:12.997494Z","pmid":"41349769","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":[]}