MYB, a proto-oncogene, is overexpressed in prostate cancer (PCa) and promotes its growth, aggressiveness, and resistance to androgen-deprivation therapy. Here, we examined the effect of androgen signaling on MYB expression and delineated the underlying molecular mechanisms. Paralleling a dichotomous effect on growth, low-dose androgen induced MYB expression at both transcript and protein levels, whereas it was suppressed in high-dose androgen-treated PCa cells. Interestingly, treatment with both low- and high-dose androgen transcriptionally upregulated MYB by increasing the binding of androgen receptor to the MYB promoter. In a time-course assay, androgen induced MYB expression at early time points followed by a sharp decline in high-dose androgen-treated cells due to decreased stability of MYB mRNA. Additionally, profiling of MYB-targeted miRNAs demonstrated significant induction of miR-150 in high-dose androgen-treated PCa cells. We observed a differential binding of androgen receptor on miR-150 promoter with significantly greater occupancy recorded in high-dose androgen-treated cells than those treated with low-dose androgen. Functional inhibition of miR-150 relieved MYB suppression by high-dose androgen, while miR-150 mimic abolished MYB induction by low-dose androgen. Furthermore, MYB-silencing or miR-150 mimic transfection suppressed PCa cell growth induced by low-dose androgen, whereas miR-150 inhibition rescued PCa cells from growth repression by high-dose androgen. Similarly, we observed that MYB silencing suppressed the expression of androgen-responsive, cell cycle–related genes in low-dose androgen-treated cells, while miR-150 inhibition increased their expression in cells treated with high-dose androgen. Overall, these findings reveal novel androgen-mediated mechanisms of MYB regulation that support its biphasic growth control in PCa cells.

MYB是一种原癌基因，在前列腺癌 (PCa) 中过度表达并促进其生长、侵袭性和对雄激素剥夺疗法的抵抗力。在这里，我们检查了雄激素信号传导对MYB表达的影响并描述了潜在的分子机制。与对生长的二分效应平行，低剂量雄激素在转录物和蛋白质水平诱导MYB表达，而在高剂量雄激素处理的 PCa 细胞中它被抑制。有趣的是，低剂量和高剂量雄激素治疗通过增加雄激素受体与MYB启动子的结合，转录上调MYB。在时程分析中，雄激素诱导MYB在早期时间点表达，随后由于MYB mRNA的稳定性降低，高剂量雄激素处理的细胞急剧下降。此外，MYB靶向 miRNA 的分析表明在高剂量雄激素处理的 PCa 细胞中 miR-150 的显着诱导。我们观察到雄激素受体在 miR-150 启动子上的差异结合，在高剂量雄激素处理的细胞中记录的占有率明显高于用低剂量雄激素处理的细胞。miR-150 的功能性抑制减轻了高剂量雄激素对MYB的抑制，而 miR-150 模拟物则消除了低剂量雄激素对MYB的诱导。此外，MYB- 沉默或 miR-150 模拟转染抑制低剂量雄激素诱导的 PCa 细胞生长，而 miR-150 抑制将 PCa 细胞从高剂量雄激素的生长抑制中拯救出来。同样，我们观察到MYB沉默抑制了低剂量雄激素处理细胞中雄激素反应性细胞周期相关基因的表达，而 miR-150 抑制增加了它们在高剂量雄激素处理细胞中的表达。总的来说，这些发现揭示了新的雄激素介导的MYB调节机制，支持其在 PCa 细胞中的双相生长控制。