BK21-4th Team, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Korea.
Biopharmaceutical research center, Ochang Institute of Biological and Environmental Science, Korea Basic Science Institute (KBSI), 162, Cheongju, 28119, Korea.
Cell Death Dis. 2024 Apr 17;15(4):274. doi: 10.1038/s41419-024-06647-0.
Accumulating evidence demonstrates that the activity regulation of ELK3, a member of the E26 transformation-specific oncogene family, is critical to regulating cell proliferation, migration, and survival in human cancers. However, the molecular mechanisms of how ELK3 induces chemoresistance in prostate cancer (PCa) have not been elucidated. In this study, we found that SPOP and ELK3 are an interacting partner. The interaction between SPOP and ELK3 resulted in increased ELK3 ubiquitination and destruction, assisted by checkpoint kinase-mediated ELK3 phosphorylation. Notably, the modulation of SPOP-mediated ELK3 protein stability affected the c-Fos-induced cell proliferation and invasion of PCa cells. The clinical involvement of the SPOP-ELK3 axis in PCa development was confirmed by an immunohistochemical assay on 123 PCa tissues, with an inverse correlation between increased ELK3 and decreased SPOP being present in ~80% of the specimens. This observation was supported by immunohistochemistry analysis using a SPOP-mutant PCa specimen. Finally, docetaxel treatment induced cell death by activating checkpoint kinase- and SPOP-mediated ELK3 degradation, while SPOP-depleted or SPOP-mutated PCa cells showed cell death resistance. Notably, this observation was correlated with the protein levels of ELK3. Taken together, our study reveals the precise mechanism of SPOP-mediated degradation of ELK3 and provides evidence that SPOP mutations contribute to docetaxel resistance in PCa.
越来越多的证据表明，E26 转化特异性致癌基因家族成员 ELK3 的活性调节对于调节人类癌症中的细胞增殖、迁移和存活至关重要。然而，ELK3 如何诱导前列腺癌（PCa）的化疗耐药性的分子机制尚未阐明。在这项研究中，我们发现 SPOP 和 ELK3 是相互作用的伙伴。SPOP 和 ELK3 之间的相互作用导致 ELK3 的泛素化和降解增加，这一过程得到了检查点激酶介导的 ELK3 磷酸化的辅助。值得注意的是，调节 SPOP 介导的 ELK3 蛋白稳定性影响了 c-Fos 诱导的 PCa 细胞的增殖和侵袭。通过对 123 例 PCa 组织进行免疫组织化学检测，证实了 SPOP-ELK3 轴在 PCa 发展中的临床参与，在约 80%的标本中，ELK3 的增加与 SPOP 的减少呈负相关。使用 SPOP 突变型 PCa 标本进行的免疫组化分析支持了这一观察结果。最后，多西紫杉醇通过激活检查点激酶和 SPOP 介导的 ELK3 降解诱导细胞死亡，而 SPOP 耗尽或 SPOP 突变的 PCa 细胞表现出对细胞死亡的抵抗。值得注意的是，这一观察结果与 ELK3 的蛋白水平相关。总之，我们的研究揭示了 SPOP 介导的 ELK3 降解的精确机制，并提供了证据表明 SPOP 突变导致 PCa 对多西紫杉醇的耐药性。
