Steroid Receptor Coactivator-3 Regulates Glucose Metabolism in Bladder Cancer Cells through Coactivation of Hypoxia Inducible Factor 1 β

被引：52

作者：

Zhao, Wei ^{[1
]}

Chang, Cunjie ^{[1
]}

Cui, Yangyan ^{[1
]}

Zhao, Xiaozhi ^{[3
,5
]}

Yang, Jun ^{[4
]}

Shen, Lan ^{[1
]}

Zhou, Ji ^{[6
]}

Hou, Zhibo ^{[7
]}

Zhang, Zhen ^{[2
]}

Ye, Changxiao ^{[3
]}

Hasenmayer, Donald ^{[8
]}

Perkins, Robert ^{[8
]}

Huang, Xiaojing ^{[1
]}

Yao, Xin ^{[6
]}

Yu, Like ^{[7
]}

Huang, Ruimin ^{[9
]}

Zhang, Dianzheng ^{[8
]}

Guo, Hongqian ^{[3
,5
]}

Yan, Jun ^{[1
,2
]}

机构：

[1] Nanjing Univ, MOE Key Lab Model Anim Dis Study, Model Anim Res Ctr, Nanjing Biomed Res Inst, Nanjing 210008, Jiangsu, Peoples R China

[2] Wenzhou Med Coll, Zhejiang Prov Key Lab Technol & Applicat Model Or, Sch Life Sci, Wenzhou 325035, Zhejiang, Peoples R China

[3] Nanjing Univ, Sch Med, Nanjing Drum Tower Hosp, Dept Urol, Nanjing 210008, Jiangsu, Peoples R China

[4] Nanjing Univ, Sch Med, Nanjing Drum Tower Hosp, Dept Pathol, Nanjing 210008, Jiangsu, Peoples R China

[5] Nanjing Urol Res Ctr, Nanjing 210008, Jiangsu, Peoples R China

[6] Nanjing Med Univ, Affiliated Hosp 1, Dept Resp Med, Nanjing 210029, Jiangsu, Peoples R China

[7] Nanjing Chest Hosp, Dept Resp Med 1, Nanjing 210029, Jiangsu, Peoples R China

[8] Philadelphia Coll Osteopath Med, Philadelphia, PA 19131 USA

[9] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2014年 / 289卷 / 16期

关键词：

Cancer; Cell Proliferation; Glycolysis; Transcription Coactivators; Tumor Metabolism; HIF1; SRC-3; Urinary Bladder Cancer; TRANSCRIPTIONAL COACTIVATOR; LACTATE-DEHYDROGENASE; UROTHELIAL CARCINOMA; SRC-3; COACTIVATOR; GENE-EXPRESSION; AIB1; PROLIFERATION; ACTIVATION; BREAST; OVEREXPRESSION;

D O I：

10.1074/jbc.M113.535989

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Background: Steroid receptor coactivator-3 (SRC-3) is frequently overexpressed in human urinary bladder cancer. Results: SRC-3 promotes urinary bladder cancer (UBC) cells proliferation through coactivating HIF1 and up-regulating the expression of genes involved in the glycolytic pathway. Conclusion: SRC-3 plays an important role in UBC development through enhancing glycolysis. Significance: Targeting SRC-3 or enzymes in glycolytic pathway could be an attractive approach in UBC therapy. 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 1 (HIF1), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1-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 HIF1 to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.

引用

页码：11219 / 11229

页数：11

共 46 条

[1] AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer [J].