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

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.