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Isolation of Cancer Stem Cells From Human Prostate Cancer Samples
Published on: March 14, 2014
SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression
Jian Ma1,2, Kun Chang1,2, Jingtao Peng3
1Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Background:
Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alterations. SPOP (Speckle-type POZ Protein) is one of the most frequently mutated genes in primary prostate cancer, suggesting that SPOP may be a potential driver of prostate cancer. The aim of this work was to investigate how SPOP mutations contribute to prostate cancer development and progression.
Methods:
To identify molecular mediators of the tumor suppressive function of SPOP, we performed a yeast two-hybrid screen in a HeLa cDNA library using the full-length SPOP as bait. Immunoprecipitation and Western Blotting were used to analyze the interaction between SPOP and ATF2. Cell migration and invasion were determined by Transwell assays. Immunohistochemistry were used to analyze protein levels in patients' tumor samples.
Results:
Here we identified ATF2 as a bona fide substrate of the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP recognizes multiple Ser/Thr (S/T)-rich degrons in ATF2 and triggers ATF2 degradation via the ubiquitin-proteasome pathway. Strikingly, prostate cancer-associated mutants of SPOP are defective in promoting ATF2 degradation in prostate cancer cells and contribute to facilitating prostate cancer cell proliferation, migration and invasion.
Conclusion:
SPOP promotes ATF2 ubiquitination and degradation, and ATF2 is an important mediator of SPOP inactivation-induced cell proliferation, migration and invasion.
Insights
Speckle-type POZ Protein (SPOP) mutations in prostate cancer disrupt the degradation of ATF2, a key protein that drives cancer cell proliferation, migration, and invasion.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Next-generation sequencing reveals frequent SPOP mutations in prostate cancer, implicating SPOP as a potential driver.
- Understanding the role of SPOP mutations in prostate cancer development and progression is crucial.
Purpose of the Study:
- To investigate the molecular mechanisms by which SPOP mutations contribute to prostate cancer.
- To identify mediators of SPOP's tumor-suppressive function.
Main Methods:
- Yeast two-hybrid screening to identify SPOP-interacting proteins.
- Immunoprecipitation, Western Blotting, Transwell assays, and immunohistochemistry were employed.
- ATF2 was identified as a substrate of the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex.
Main Results:
- SPOP targets ATF2 for degradation via the ubiquitin-proteasome pathway by recognizing specific degrons.
- Prostate cancer-associated SPOP mutants exhibit impaired ATF2 degradation.
- Defective ATF2 degradation by mutant SPOP promotes prostate cancer cell proliferation, migration, and invasion.
Conclusions:
- SPOP facilitates ATF2 ubiquitination and degradation, acting as a tumor suppressor.
- ATF2 is a critical mediator of cellular changes induced by SPOP inactivation in prostate cancer.
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