SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression

Journal of Experimental & Clinical Cancer Research : CR
Jian MaChenji Wang

Abstract

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. 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. 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,...Continue Reading

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Citations

Dec 24, 2018·International Journal of Molecular Sciences·Dana PascoviciMehdi Mirzaei
Jan 7, 2020·Molecular Cancer·Yizuo SongXueqiong Zhu
Sep 5, 2020·International Journal of Molecular Sciences·Gizem CelebiOzlem Kutlu
May 2, 2020·Nature Reviews. Urology·Zhiwei WangWenyi Wei
Dec 11, 2020·Cancer Cell International·Jian LiuYamei Pang
Jun 27, 2021·Pharmacology & Therapeutics·Maria Adamaki, Vassilios Zoumpourlis
Aug 27, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xin XuYili Yang
Oct 2, 2021·Proceedings of the National Academy of Sciences of the United States of America·Carley SnoznikTodd Lamitina

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Methods Mentioned

BETA
ubiquitination
transfection
immunoprecipitation
two-hybrid
co-immunoprecipitation
co-IP

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