Triglyceride lipase PNPLA2–independent suppression of c-MYC signaling by the metabolic coactivator ABHD5 in prostate cancer

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.