title: Steroid receptor coactivator-3 regulates glucose metabolism in bladder cancer cells through coactivation of hypoxia inducible factor 1α.
abstract: Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as "Warburg effect," to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Cunjie
authors.initials: C
authors.lastname: Chang
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Yangyan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Departments of Urology and Nanjing University, Nanjing, Jiangsu 210008, China; Nanjing Urology Research Center, Nanjing, Jiangsu 210008, China.
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Pathology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing University, Nanjing, Jiangsu 210008, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, China.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Hou
authors.affiliation: the Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Departments of Urology and Nanjing University, Nanjing, Jiangsu 210008, China.
authors.forename: Changxiao
authors.initials: C
authors.lastname: Ye
authors.affiliation: Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania 19131, and.
authors.forename: Donald
authors.initials: D
authors.lastname: Hasenmayer
authors.affiliation: Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania 19131, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Perkins
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, China.
authors.forename: Like
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065.
authors.forename: Ruimin
authors.initials: R
authors.lastname: Huang
authors.affiliation: Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania 19131, and.
authors.forename: Dianzheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Departments of Urology and Nanjing University, Nanjing, Jiangsu 210008, China; Nanjing Urology Research Center, Nanjing, Jiangsu 210008, China,. Electronic address: dr.ghq@163.com.
authors.forename: Hongqian
authors.initials: H
authors.lastname: Guo
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, Jiangsu 210061, China,; the Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China,. Electronic address: yanjun@nju.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis / Q000235:genetics; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D010735:Phosphoglycerate Kinase / Q000096:biosynthesis / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D018809:Proliferating Cell Nuclear Antigen; C495677:SLC2A1 protein, human; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C577282:PGK1 protein, human; D010735:Phosphoglycerate Kinase
keywords: Cancer; Cell Proliferation; Glycolysis; HIF1α; SRC-3; Transcription Coactivators; Tumor Metabolism; Urinary Bladder Cancer