Background
Prostate cancer (PCa), an inert tumour, has a long progression period, but valid biomarkers and
Conclusions
Acetylation of extracellular K620 on LIFR reinforces its homodimerization and integrates the activities of PDPK1, AKT, GSK3β and GCN5 to form a novel positive feedback loop in PCa; this modification is thus a promising biomarker for monitoring PCa progression.
Methods
The posttranscriptional regulation of leukaemia inhibitory factor receptor (LIFR) and its novel downstream signalling activity in PCa were studied using liquid mass spectrometry, genetically engineered mouse (GEM) models, organoid assays, lentivirus packaging, infection and stable cell line construction.
Results
In this study, the level of acetylated K620 on LIFR in its extracellular domain was shown to predict the progression and prognosis of PCa. In PCa cells, LIFR-K620 acetylation is reversibly mediated by GCN5 and SIRT2. GEM experiments and organoid assays confirmed that the loss of LIFR-K620 acetylation inhibits PCa progression. Mechanistically, K620 acetylation facilitates LIFR homodimerization and subsequently promotes LIFR-S1044 phosphorylation and activation, which further recruits PDPK1 to activate AKT signalling and sequentially enhances the GCN5 protein level to sustain the protumour level of LIFR-K620 acetylation by preventing GCN5 degradation via CRL4Cdt2 E3 ligase. Conclusions: Acetylation of extracellular K620 on LIFR reinforces its homodimerization and integrates the activities of PDPK1, AKT, GSK3β and GCN5 to form a novel positive feedback loop in PCa; this modification is thus a promising biomarker for monitoring PCa progression.