PO.MCB07.01 · 分子与细胞生物学
IL-6/STAT3信号介导前列腺癌中MYB的失调：对侵袭性疾病进展和种族差异的意义
IL-6/STAT3 signaling mediates MYB dysregulation in prostate cancer: Implications for aggressive disease progression and racial disparities
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摘要 Abstract
中文摘要
我们此前已报道MYB在前列腺癌的进展、侵袭性和治疗耐药中的作用。值得注意的是，我们还观察到MYB表达存在种族差异，黑人患者的前列腺癌中MYB水平较高，且与晚期肿瘤分级和更短的生化复发时间相关。在本研究中，我们探讨了前列腺癌中MYB失调的分子机制，这可能与其在黑人患者中的较高水平相关。我们发现黑人前列腺癌患者血清IL-6水平显著升高，用IL-6处理前列腺癌细胞系导致MYB表达以剂量和时间依赖的方式上调。当细胞预先用IL-6中和抗体（Tocilizumab）或STAT3抑制剂（Stattic）处理时，IL-6诱导的MYB上调被消除。值得注意的是，AR阴性细胞系表现出高的基础MYB表达，Tocilizumab处理使其略微降低，而STAT3抑制则使其大幅降低，提示STAT3是前列腺癌中MYB过表达的重要调控因子。染色质免疫沉淀（ChIP）分析显示，IL-6处理后STAT3与MYB第一内含子区域的结合增加，而预先用Tocilizumab或Stattic处理后该结合减少。此外，在该区域我们观察到CDK9（P-TEFb复合物的关键组分）的募集增强，CDK9被证明通过RNA聚合酶II羧基末端结构域的Ser2磷酸化促进MYB转录暂停的释放。用CDK9抑制剂预处理前列腺癌细胞也减弱了IL-6诱导的MYB表达。最后，沉默MYB或用CDK9抑制剂处理细胞显著削弱了IL-6介导的前列腺癌细胞增殖、迁移和侵袭。这些发现确立了IL-6/STAT3信号是前列腺癌中MYB表达的关键调控因子，凸显了其在前列腺癌发病机制和种族差异中的潜在作用。
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We have previously reported a role for MYB in the progression, aggressiveness, and therapy resistance of prostate cancer. Notably, we also observed racially disparate MYB expression, with higher levels being present in prostate cancer from Black patients, correlating with advanced tumor grade and shorter time to biochemical recurrence. In this study, we investigated the molecular mechanisms underlying MYB dysregulation in prostate cancer that could potentially be linked to its higher levels in Black patients. We found that serum levels of IL-6 were significantly elevated in Black patients with prostate cancer, and treatment of prostate cancer cell lines with IL-6 resulted in a dose- and time-dependent upregulation of MYB expression. IL-6-induced MYB upregulation was abolished when cells were pre-treated with either an IL-6 neutralizing antibody (Tocilizumab) or a STAT3 inhibitor (Stattic). Notably, AR-negative cell lines exhibited high basal MYB expression, which was slightly reduced by Tocilizumab treatment but drastically reduced upon STAT3 inhibition, suggesting that it is a significant regulator of MYB overexpression in prostate cancer. Chromatin immunoprecipitation (ChIP) analysis revealed increased STAT3 binding to the MYB in the first intronic region, following IL-6 treatment, which was reduced upon pre-treatment with Tocilizumab or Stattic. Additionally, in this region, we observed enhanced recruitment of CDK9, a key component of the P-TEFb complex, which is shown to facilitate the release of the MYB transcriptional pause through Ser2 phosphorylation in the c-terminal domain of RNA polymerase II. Pre-treatment of prostate cancer cells with a CDK9 inhibitor also attenuated IL-6-induced MYB expression. Finally, silencing MYB or treating cells with a CDK9 inhibitor significantly impaired IL-6-mediated proliferation, migration, and invasion of prostate cancer cells. These findings establish IL-6/STAT3 signaling as a critical regulator of MYB expression in prostate cancer, highlighting its potential role in prostate cancer pathogenesis and racial disparities.
利益披露 Disclosure
V. Ellu Valappil, None..
S. Anand, None..
K. Vikramdeo, None..
R. Mitra, None..
S. Singh, None..
A. P. Singh, None.