biostudies-literatureUnknown10(9)Maranto CAndrogen receptor (AR) drives prostate cancer (PC) growth and progression, and targeting AR signaling is the mainstay of pharmacological therapies for PC. Resistance develops relatively fast as a result of refueled AR activity. A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR expression in castrate-resistant PC (CRPC). This study uncovers an unexpected function of active Stat5 signaling, a known promoter of PC growth and clinical progression, as a potent inducer of <i>AR</i> gene transcription. Stat5 suppression inhibited <i>AR</i> gene transcription in preclinical PC models and reduced the levels of wild-type, mutated, and truncated AR proteins. Pharmacological Stat5 inhibition by a specific small-molecule Stat5 inhibitor down-regulated Stat5-inducible genes as well as AR and AR-regulated genes and suppressed PC growth. This work introduces the concept of Stat5 as an inducer of <i>AR</i> gene transcription in PC. Pharmacological Stat5 inhibitors may represent a new strategy for suppressing AR and CRPC growth.Science advanceseadi2742https://www.ebi.ac.uk/biostudies/studies/S-EPMC10901378biostudies-literatureStat5 induces androgen receptor (<i>AR</i>) gene transcription in prostate cancer and offers a druggable pathway to target AR signaling.PMC10901378Udhane VMcCluskey BJohnson SQi SBanerjee ASabharwal LWang LMaranto CPitzen SPIczkowski KANevalainen MTDevi SDehm SMO'Connor CJacobsohn KfalseStat5 induces androgen receptor (<i>AR</i>) gene transcription in prostate cancer and offers a druggable pathway to target AR signaling.Androgen receptor (AR) drives prostate cancer (PC) growth and progression, and targeting AR signaling is the mainstay of pharmacological therapies for PC. Resistance develops relatively fast as a result of refueled AR activity. A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR expression in castrate-resistant PC (CRPC). This study uncovers an unexpected function of active Stat5 signaling, a known promoter of PC growth and clinical progression, as a potent inducer of <i>AR</i> gene transcription. Stat5 suppression inhibited <i>AR</i> gene transcription in preclinical PC models and reduced the levels of wild-type, mutated, and truncated AR proteins. Pharmacological Stat5 inhibition by a specific small-molecule Stat5 inhibitor down-regulated Stat5-inducible genes as well as AR and AR-regulated genes and suppressed PC growth. This work introduces the concept of Stat5 as an inducer of <i>AR</i> gene transcription in PC. Pharmacological Stat5 inhibitors may represent a new strategy for suppressing AR and CRPC growth.2024-01-01T00:00:00Z2024 Mar2025-04-22T06:39:45.073Z2025-04-05T21:49:03.065ZS-EPMC109013783841682210.1126/sciadv.adi2742