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Identifying reliable biomarkers and understanding their underlying mechanisms is crucial for advancing clinical management.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Firstly, we integrated single-cell and bulk transcriptomic data and employed the\n                      <jats:italic>Scissor<\/jats:italic>\n                      tool to characterize tumor cells with metastatic advantages (termed metastatic cells). Then, independent predictive genes for metastasis were identified through univariate and multivariate regression analyses. The role of hub genes in PCa metastasis was further validated using multiple large datasets, malignant phenotype experiments, in vivo metastatic models, and a clinical-sample-based immunohistochemical cohort. Further, we explored the metabolic characteristics related to hub genes through unbiased functional annotation, and validated the upregulated glycolysis by measuring\n                      <jats:sc>l<\/jats:sc>\n                      -lactic acid production, extracellular acidification rates (ECAR), and oxygen consumption rates (OCR). Finally, multi-omics data were employed to investigate the promoter-methylation-dependent regulation of alpha-2-glycoprotein 1 (\n                      <jats:italic>AZGP1<\/jats:italic>\n                      ) transcription, with methylation confirmed through PCa cell-based methylation-specific PCR (MSP) assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>AZGP1<\/jats:italic>\n                      was identified as an independent protective predictor of metastasis, which was validated in vitro and in vivo. Metabolic functional annotation revealed that glycolysis was upregulated in\n                      <jats:italic>AZGP1<\/jats:italic>\n                      -positive luminal cells. Consistently, overexpression of\n                      <jats:italic>AZGP1<\/jats:italic>\n                      in PCa cells was associated with lower\n                      <jats:sc>l<\/jats:sc>\n                      -lactic acid levels, reduced ECAR, and increased OCR. In addition, DNA methylation at the cg26429636 region was linked to decreased transcriptional expression of\n                      <jats:italic>AZGP1<\/jats:italic>\n                      . MSP assays revealed an unmethylated pattern in PCa cells with high\n                      <jats:italic>AZGP1<\/jats:italic>\n                      expression, and higher methylation levels in\n                      <jats:italic>AZGP1<\/jats:italic>\n                      -low cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Promoter methylation of\n                      <jats:italic>AZGP1<\/jats:italic>\n                      leads to reduced transcriptional expression, thereby promoting glycolysis in tumor cells and facilitating metastasis. The detection of\n                      <jats:italic>AZGP1<\/jats:italic>\n                      methylation levels offers a valuable reference for dynamic surveillance of PCa metastasis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s11658-025-00818-3","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T09:54:09Z","timestamp":1768384449000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Methylation-induced silencing of AZGP1 enhances prostate cancer metastasis by stimulating tumoral glycolysis"],"prefix":"10.1186","volume":"31","author":[{"given":"Lu","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinguang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linyue","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4993-0500","authenticated-orcid":false,"given":"Xiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"818_CR1","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.ccell.2016.09.011","volume":"30","author":"Y Liu","year":"2016","unstructured":"Liu Y, Cao X. 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KY-2024-065).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication was obtained from all participants.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Authors declare no Competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5"}}