Qi Mei, Hu Jing, Cui Yanyi, Jiao Meng, Feng Tingting, Li Xinjun, Pang Yu, Chen Xinyi, Qin Ruixi, Su Peng, Zhang Hui, Wang Yan, Gong Yaoqin, Han Bo
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, Shandong University, School of Basic Medical Sciences, 250012, Jinan, China.
Department of Pathology, Shandong University Qi Lu Hospital, 250012, Jinan, China.
Oncogenesis. 2019 Mar 14;8(3):23. doi: 10.1038/s41389-019-0131-5.
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.
在前列腺癌（PCa）管理中，如何区分惰性疾病和侵袭性疾病仍然是一个巨大的挑战。Cullin 4B（CUL4B）是一种支架蛋白，在多种人类恶性肿瘤中表现出致癌活性。在本研究中，我们利用PCa组织标本、细胞系和异种移植模型来确定CUL4B是否促进PCa的进展和转移。在此，我们表明CUL4B表达与PCa的侵袭性高度相关。CUL4B表达促进PCa细胞的增殖、上皮-间质转化和转移潜能，而敲低CUL4B则起抑制作用。机制上，CUL4B通过对miR-204的表观遗传沉默正向调节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，从而形成一个正反馈环。临床上，CUL4B+/SOX4+定义了一组预后不良的PCa患者。生物信息学分析进一步揭示，Wnt/β-连环蛋白激活特征在CUL4B+/SOX4+患者亚组中富集。有趣的是，Wnt抑制剂在体外和体内均显著减弱CUL4B的致癌能力。总之，我们的研究通过与SOX4相互作用的正反馈环将CUL4B鉴定为侵袭性PCa的关键调节因子。这种调节回路可能在PCa进展中起关键作用。
