ELK3 destabilization by speckle-type POZ protein suppresses prostate cancer progression and docetaxel resistance.

Abstract

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.

• Authors: Cheol-Jung Lee, Heejung Lee, Seo Ree Kim, Soo-Bin Nam, Ga-Eun Lee, Kyeong Eun Yang, Guk Jin Lee, Sang Hoon Chun, Han Chang Kang, Joo Young Lee, Hye Suk Lee, Sung-Jun Cho, Yong-Yeon Cho
• Journal: Cell death & disease (Cell Death Dis) Vol. 15 Issue 4 Pg. 274 (Apr 17 2024) ISSN: 2041-4889 [Electronic] England
• PMID: 38632244 (Publication Type: Journal Article)
• Copyright: © 2024. The Author(s).

Chemical References

• Docetaxel
• Nuclear Proteins
• Proto-Oncogene Proteins c-fos
• Repressor Proteins
• SPOP protein, human
• Elk3 protein, human
• Proto-Oncogene Proteins c-ets

Topics

• Humans
• Male
• Docetaxel (pharmacology, therapeutic use)
• Mutation
• Nuclear Proteins (metabolism)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-fos (metabolism)
• Repressor Proteins (metabolism)
• Ubiquitination
• Proto-Oncogene Proteins c-ets (metabolism)
• Drug Resistance, Neoplasm (genetics)