SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression

Abstract

BackgroundNext-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.MethodsTo 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.ResultsHere 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.ConclusionSPOP promotes ATF2 ubiquitination and degradation, and ATF2 is an important mediator of SPOP inactivation-induced cell proliferation, migration and invasion.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0809-0) contains supplementary material, which is available to authorized users.

The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells

“…In particular, ATF2 has been shown to be capable of activating g-globin. 27 Moreover, NRF2 has been reported to be regulated by the CUL3 ubiquitin ligase complex 28 and might be a transcriptional activator of g-globin. 29 We first tested whether SPOP regulates the amounts of any of these proteins in erythroid cells.…”

Immune-Related Gene-Based Novel Subtypes to Establish a Model Predicting the Risk of Prostate Cancer

“…Speckle-type POZ Protein can inhibit the proliferation, migration, and invasion of PCa cells by promoting ATF2 ubiquitination (Ma et al, 2018). PCa-associated SPOP mutants are defective at promoting ATF2 degradation in PCa cells and contribute to facilitating PCa cell proliferation, migration, and invasion (Ma et al, 2018).…”

“…Speckle-type POZ Protein can inhibit the proliferation, migration, and invasion of PCa cells by promoting ATF2 ubiquitination (Ma et al, 2018). PCa-associated SPOP mutants are defective at promoting ATF2 degradation in PCa cells and contribute to facilitating PCa cell proliferation, migration, and invasion (Ma et al, 2018). Expressing PCa-associated SPOP mutants or knocking out SPOP gives PCa cells resistance to cell death caused by stress granule inducers such as docetaxel, sodium FIGURE 9 | Decision curve analyses suggested that the model had good clinical benefits: (A) The model had higher net benefit and wider threshold probability range.…”

The emerging role of SPOP protein in tumorigenesis and cancer therapy

“…SPOP suppresses tumorigenesis and progression via regulation of cell growth, apoptosis, migration, invasion and drug resistance by targeting its downstream substrates in several types of human malignancies, including prostate, lung, gastric, liver, colon and endometrial cancers SPOP mutations and downregulation were detected in human PrCa tissues, and these mutations were also tightly correlated with a worse prognosis in patients with PrCa [61]. More importantly, extensive biochemical evidence has further indicated that SPOP functions as a tumor suppressor by promoting the degradation of oncogenic substrates in PrCa, including SRC3 [62], AR [63], TRIM24 [64], c-Myc [65], DEK [66], SENP7 [67], EglN2 [68], ATF2 [69], Cdc20 [70], ERG [71,81], BRD4 [72][73][74], PD-L1 [75] and cyclin E1 [76]. Due to the many publications and space limitations, we will not describe the tumor suppressive role that SPOP plays by promoting the ubiquitination and degradation of its substrates in PrCa in detail.…”