Smad3, a central regulator of energy reprogramming, has been reported to regulate HIF-1α expression to promote tumor glycolysis in prostate cancer cells [20], and phosphorylation of Smad3 linker domain, including Ser213, Ser204, Ser208 and Thr179, indirectly inhibits its COOH– terminal phosphorylation and subsequently suppresses tumor-suppressive pSmad3C signaling, generating resistance to the growth-inhibitory effect of TGF-β [33, 43–45]. This evidence concerns the gene SMAD3 and Familial prostate cancer.