Mitochondrial pyruvate carrier 1 (MPC1) and MPC 2 form a transporter complex in cells to control pyruvate transportation into mitochondria. Reduced expression of MPC1 disrupts the transporter function, induces metabolic shift to increase glycolysis, and thus plays important roles in several diseases, including cancer. However, the role of MPC1 in prostate cancer and the underlying mechanism causing the down-regulation of MPC1 in tumor cells remain to be defined. Here, we show that MPC1 serves as a critical regulator of glycolysis in prostate cancer cells, which in turn controls cancer cell growth, invasion, and the tumorigenic capability. More importantly, we identified that chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a steroid receptor superfamily member, transcriptionally regulates the expression of MPC1. We further demonstrate that COUP-TFII, which is upregulated in the prostate cancer patient, regulates MPC1 and glycolysis to promote tumor growth and metastasis. Our findings reveal that COUP-TFII represses MPC1 expression in prostate cancer cells to facilitate a metabolism switch to increase glycolysis and promote cancer progression. This observation raises an intriguing possibility of targeting COUP-TFII to modulate cancer cell metabolism for prostate cancer intervention.