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Oncogenesis. 2019 Mar 14;8(3):23. doi: 10.1038/s41389-019-0131-5.

CUL4B promotes prostate cancer progression by forming positive feedback loop with SOX4.

Qi M1,2, Hu J1, Cui Y3, Jiao M1, Feng T1, Li X1,4, Pang Y1,5, Chen X1,6, Qin R2, Su P2, Zhang H2, Wang Y2, Gong Y7, Han B8,9.

Author information

1
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, Shandong University, School of Basic Medical Sciences, 250012, Jinan, China.
2
Department of Pathology, Shandong University Qi Lu Hospital, 250012, Jinan, China.
3
Department of Urology, The Fourth People's Hospital of Jinan, 250031, Jinan, China.
4
Department of Pathology, Binzhou People's Hospital, 256610, Binzhou, China.
5
Department of Pathology, Taian City Central Hospital, 271000, Taian, China.
6
Department of Pathology, The Affiliated Central Hospital of Qingdao University Medical College, 266042, Qingdao, China.
7
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University, School of Basic Medical Sciences, 250012, Jinan, China.
8
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, Shandong University, School of Basic Medical Sciences, 250012, Jinan, China. boh@sdu.edu.cn.
9
Department of Pathology, Shandong University Qi Lu Hospital, 250012, Jinan, China. boh@sdu.edu.cn.

Abstract

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.

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