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: Wei Zhao, Cunjie Chang, Yangyan Cui, Xiaozhi Zhao, Jun Yang, Lan Shen, Ji Zhou, Zhibo Hou, Zhen Zhang, Changxiao Ye, Donald Hasenmayer, Robert Perkins, Xiaojing Huang, Xin Yao, Like Yu, Ruimin Huang, Dianzheng Zhang, Hongqian Guo, Jun Yan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 16 Pg. 11219-11229 (Apr 18 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24584933 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucose Transporter Type 1
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• Proliferating Cell Nuclear Antigen
• SLC2A1 protein, human
• NCOA3 protein, human
• Nuclear Receptor Coactivator 3
• PGK1 protein, human
• Phosphoglycerate Kinase

Topics

• Animals
• Cell Hypoxia (genetics)
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Glucose Transporter Type 1 (biosynthesis, genetics)
• Glycolysis
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Male
• Mice
• Neoplasm Proteins (genetics, metabolism)
• Nuclear Receptor Coactivator 3 (genetics, metabolism)
• Phosphoglycerate Kinase (biosynthesis, genetics)
• Proliferating Cell Nuclear Antigen (genetics, metabolism)
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)