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The in vivo effects of CEBPD overexpression in a high\u2010glucose environment on tumour growth were investigated in xenografted induced diabetic severe combined immunodeficiency\/beige mice. Data mining was used to cross\u2010validate the associations between <jats:italic>CEBPD<\/jats:italic> and <jats:italic>MYC<\/jats:italic> copy number and transcriptional expression, quantitative reverse transcription\u2010polymerase chain reaction, immunohistochemistry, chromogenic in situ hybridization, and in situ hybridization targeting microRNA were performed on 635 UC patient samples and xenograft samples. UC patient survival in relation to diabetes was validated by using the National Health Insurance Research Database.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>CEBPD<\/jats:italic> and <jats:italic>MYC<\/jats:italic> coamplification (29.6%) occurred at a high frequency, MYC expression promoted chromosomal instability, facilitating <jats:italic>CEBPD<\/jats:italic> copy number gain and expression. CEBPD promoted glucose uptake and lactate production by upregulating SLC2A1 and HK2, leading to mitochondrial fission, increased extracellular acidification rate and decreased oxygen consumption rate to fuel cell growth. CEBPD upregulated HK2 expression through multiple regulation pathways including MYC stabilization, suppression of <jats:italic>FBXW7<\/jats:italic> transactivation and MYC\u2010independent transcriptional suppression of hsa\u2010miR\u2010429. Clinical and xenografted experiments confirmed the growth advantage of CEBPD in relation to glucose metabolic dysregulation and the significant correlations between the expression of these genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We confirmed that CEBPD has an oncogenic role in UC by activating AKT signalling and initiating metabolic reprogramming from mitochondrial oxidative phosphorylation to glycolysis to satisfy glucose addiction. These novel CEBPD\u2010 and MYC\u2010centric multilayered positive feedback loops enhance cancer growth that could complement theranostic approaches.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.674","type":"journal-article","created":{"date-parts":[[2021,12,26]],"date-time":"2021-12-26T16:50:29Z","timestamp":1640537429000},"source":"Crossref","is-referenced-by-count":17,"title":["Biological significance of <i>MYC<\/i> and <i>CEBPD<\/i> coamplification in urothelial carcinoma: Multilayered genomic, transcriptional and posttranscriptional positive feedback loops enhance oncogenic glycolysis"],"prefix":"10.1002","volume":"11","author":[{"given":"Ti\u2010Chun","family":"Chan","sequence":"first","affiliation":[{"name":"Department of Medical Research Chi Mei Medical Center  Tainan Taiwan"},{"name":"National Institute of Cancer Research National Health Research Institutes  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Bioindustry Sciences College of Bioscience and Biotechnology National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kien Thiam","family":"Tan","sequence":"additional","affiliation":[{"name":"ACT Genomics Co., Ltd.  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