Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study invest...Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer(HSPC)through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.Methods:HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation,invasion,migration,and epithelial-mesenchymal transition.Xenograft assays,bioinformatic screening,and analyses of O-GlcNAcylation and protein stability were performed,together with quantitative polymerase chain reaction(qPCR)and Western blotting.Results:ONX-0914 markedly suppressed hormone-sensitive prostate cancer(HSPC)progression through both LMP7-dependent and LMP7-independent mechanisms.Mechanistically,ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation,leading to stabilization of the transcriptional repressor Transcription factor 7-like 1(TCF7L1)and consequent suppression of androgen receptor(AR)expression.Functionally,activation of the O-GlcNAcylation-TCF7L1 axis inhibited cell proliferation,invasion,migration,and epithelial-mesenchymal transition in vitro.In vivo,TCF7L1 overexpression,particularly under conditions of enhanced O-GlcNAcylation,significantly suppressed tumor growth and AR expression.Conclusion:This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1,leading to repression of AR signaling and inhibition of HSPC progression.These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.展开更多
文摘Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer(HSPC)through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.Methods:HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation,invasion,migration,and epithelial-mesenchymal transition.Xenograft assays,bioinformatic screening,and analyses of O-GlcNAcylation and protein stability were performed,together with quantitative polymerase chain reaction(qPCR)and Western blotting.Results:ONX-0914 markedly suppressed hormone-sensitive prostate cancer(HSPC)progression through both LMP7-dependent and LMP7-independent mechanisms.Mechanistically,ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation,leading to stabilization of the transcriptional repressor Transcription factor 7-like 1(TCF7L1)and consequent suppression of androgen receptor(AR)expression.Functionally,activation of the O-GlcNAcylation-TCF7L1 axis inhibited cell proliferation,invasion,migration,and epithelial-mesenchymal transition in vitro.In vivo,TCF7L1 overexpression,particularly under conditions of enhanced O-GlcNAcylation,significantly suppressed tumor growth and AR expression.Conclusion:This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1,leading to repression of AR signaling and inhibition of HSPC progression.These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.
