Biphasic transcriptional and posttranscriptional regulation of MYB by androgen signaling mediates its growth control in prostate cancer.
Biphasic transcriptional and posttranscriptional regulation of MYB by androgen signaling mediates its growth control in prostate cancer.
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通过雄激素信号传导对MYB的双相转录和转录后调节介导了其在前列腺癌中的生长控制。
DOI：
10.1016/j.jbc.2022.102725
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发表时间：
2023-01
影响因子：
4.8
通讯作者：
Singh, Ajay Pratap
中科院分区：
文献类型：
--
作者：
Acharya, Srijan;Anand, Shashi;Khan, Mohammad Aslam;Zubair, Haseeb;Srivastava, Sanjeev Kumar;Singh, Seema;Singh, Ajay Pratap
MYB是一种原癌基因，在前列腺癌（PCa）中过表达，并促进其生长，侵袭性和对雄激素剥夺疗法的抵抗。在这里，我们研究了雄激素信号对MYB表达的影响，并描绘了潜在的分子机制。除了对生长的二分效应外，低剂量雄激素诱导MYB在转录和蛋白水平的表达，而在高剂量雄激素处理的PCa细胞中，MYB的表达被抑制。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启动子的结合来转录上调MYB。在一个时间进程的分析，雄激素诱导MYB的表达在早期的时间点，随后急剧下降，在高剂量雄激素处理的细胞，由于MYB mRNA的稳定性下降。此外，MYB靶向miRNA的分析表明，高剂量雄激素处理的PCa细胞中miR-150的显著诱导。我们观察到雄激素受体对miR-150启动子的差异结合，高剂量雄激素处理的细胞中记录的占用率显著高于低剂量雄激素处理的细胞。功能性抑制miR-150可缓解高剂量雄激素对MYB的抑制，而miR-150模拟物可消除低剂量雄激素对MYB的诱导。此外，MYB沉默或miR-150模拟转染抑制了低剂量雄激素诱导的PCa细胞生长，而miR-150抑制则使PCa细胞免于高剂量雄激素的生长抑制。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响应性细胞周期相关基因的表达，而miR-150抑制增加了高剂量雄激素处理细胞中雄激素响应性细胞周期相关基因的表达。总体而言，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。
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.
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影响因子：
3.7
作者：
Huang S;Chen Y;Wu W;Ouyang N;Chen J;Li H;Liu X;Su F;Lin L;Yao Y
通讯作者：
Yao Y
影响因子：
4.6
作者：
Bhagirath D;Liston M;Akoto T;Lui B;Bensing BA;Sharma A;Saini S
通讯作者：
Saini S
影响因子：
4.6
作者：
Miree O;Srivastava SK;Khan MA;Sameeta F;Acharya S;Ndetan H;Singh KP;Hertweck KL;Dasgupta S;da Silva LM;Rocconi RP;Carter JE;Singh S;Singh AP
通讯作者：
Singh AP
DOI：
10.1006/bbrc.2001.4738
发表时间：
2001-04-27
影响因子：
3.1
作者：
Hofman, K;Swinnen, JV;Heyns, W
通讯作者：
Heyns, W
影响因子：
64.5
作者：
MOELLING, K;PFAFF, E;GRAF, T
通讯作者：
GRAF, T