Oncogenesis ( IF 6.2 ) Pub Date : 2019-03-14 , DOI: 10.1038/s41389-019-0131-5 Mei Qi , Jing Hu , Yanyi Cui , Meng Jiao , Tingting Feng , Xinjun Li , Yu Pang , Xinyi Chen , Ruixi Qin , Peng Su , Hui Zhang , Yan Wang , Yaoqin Gong , Bo Han
How to distinguish indolent from aggressive disease remains a great challenge in prostate cancer (PCa) management. Cullin 4B (CUL4B) is a scaffold protein and exhibits oncogenic activity in a variety of human malignancies. In this study, we utilized PCa tissue specimens, cell lines and xenograft models to determine whether CUL4B contributes to PCa progression and metastasis. Here, we show that CUL4B expression highly correlates with the aggressiveness of PCa. CUL4B expression promotes proliferation, epithelial−mesenchymal transition, and metastatic potential of PCa cells, whereas CUL4B knockdown inhibits. Mechanically, CUL4B positively regulates SOX4, a key regulator in PCa, through epigenetic silencing of miR-204. In turn, SOX4 upregulates CUL4B expression through transcriptional activation, thereby fulfilling a positive feedback loop. Clinically, CUL4B+/SOX4+ defines a subset of PCa patients with poor prognosis. Bioinformatics analysis further reveals that Wnt/ß-catenin activation signature is enriched in CUL4B+/SOX4+ patient subgroup. Intriguingly, Wnt inhibitors significantly attenuates oncogenic capacities of CUL4B in vitro and in vivo. Together, our study identifies CUL4B as a key modulator of aggressive PCa by a positive feedback loop that interacts with SOX4. This regulatory circuit may have a crucial role in PCa progression.
中文翻译:
CUL4B通过与SOX4形成正反馈回路来促进前列腺癌的进展
如何区分惰性疾病与侵袭性疾病仍然是前列腺癌(PCa)管理中的巨大挑战。Cullin 4B(CUL4B)是一种支架蛋白,在多种人类恶性肿瘤中均表现出致癌活性。在这项研究中,我们利用PCa组织标本,细胞系和异种移植模型来确定CUL4B是否有助于PCa的进展和转移。在这里,我们表明CUL4B表达与PCa的侵略性高度相关。CUL4B的表达促进PCa细胞的增殖,上皮间质转化和转移潜能,而CUL4B的抑制则受到抑制。从机械上讲,CUL4B通过miR-204的表观遗传沉默来积极调节PCa中的关键调节因子SOX4。反过来,SOX4通过转录激活上调CUL4B表达,从而实现正反馈回路。临床上 CUL4B + / SOX4 +定义了预后较差的PCa患者的子集。生物信息学分析进一步揭示了CUL4B + / SOX4 +患者亚组中Wnt /β-catenin激活信号丰富。有趣的是,Wnt抑制剂在体外和体内都会大大减弱CUL4B的致癌能力。总之,我们的研究通过与SOX4相互作用的正反馈回路将CUL4B鉴定为攻击性PCa的关键调节剂。该调节电路可能在PCa进程中起关键作用。我们的研究通过与SOX4相互作用的正反馈回路将CUL4B鉴定为侵略性PCa的关键调节剂。该调节电路可能在PCa进程中起关键作用。我们的研究通过与SOX4相互作用的正反馈回路将CUL4B鉴定为侵略性PCa的关键调节剂。该调节电路可能在PCa进程中起关键作用。