SPOP suppresses prostate cancer through regulation of CYCLIN E1 stability

• Published in: Cell death and differentiation Vol. 26; no. 6; pp. 1156 - 1168
• Main Authors: Ju, Lin-Gao, Zhu, Yuan, Long, Qiao-Yun, Li, Xue-Jing, Lin, Xiang, Tang, Shan-Bo, Yin, Lei, Xiao, Yu, Wang, Xing-Huan, Li, Lianyun, Zhang, Lei, Wu, Min
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2019; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/31; 13/89; 38/39; 631/45/612/1244; 631/67/1244; 64; 64/60; 96; 96/35; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Line; Cell Movement; Cell Proliferation; Cyclin E - genetics; Cyclin E - metabolism; Cyclin-dependent kinase 2; Humans; Life Sciences; Male; Nuclear Proteins - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Stability; Repressor Proteins - metabolism; Signal Transduction; Stem Cells; Substrate specificity; Tumor cell lines; Tumorigenesis; Ubiquitination
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/s41418-018-0198-0

SPOP is one of the important subunits for CUL3/SPOP/RBX1 complex tightly connected with tumorigenesis. However, its exact roles in different cancers remain debatable. Here, we identify CYCLIN E1, as a novel substrate for SPOP. SPOP directly interacts with CYCLIN E1 and specific regulates its stability in prostate cancer cell lines. SPOP/CUL3/RBX1 complex regulates CYCLIN E1 stability through poly-ubiquitination. CDK2 competes with SPOP for CYCLIN E1 interaction, suggesting that SPOP probably regulates the stability of CDK2-free CYCLIN E1. CYCLIN E1 expression rescued proliferation, migration, and tumor formation of prostate cancer cell suppressed by SPOP. Furthermore, we found SPOP selectively regulates the substrates’ stability and signaling pathways in prostate cancer and CCRC cell lines, suggesting that complicated mechanisms exist for SPOP to regulate substrate specificity. Altogether, we have revealed a novel mechanism for SPOP in suppressing prostate cancer and provided evidence to show SPOP has dual functions in prostate cancer and CCRC.