Similar Datasets
Project description:TRIM24 is an effector substrate of the E3 ubiquitin ligase adaptor SPOP and becomes stabilized in prostate cancer (PCa) with SPOP mutations. However, how TRIM24 protein is regulated in the vast majority of SPOP-wildtype PCa is unknown. Here we report TRIM28 as a critical upstream regulator of TRIM24. TRIM28 protein interacts with TRIM24 to prevent its ubiquitination and degradation by SPOP. Further, TRIM28 facilitates TRIM24 occupancy on the chromatin and, like TRIM24, augments AR signaling. TRIM28 promotes PCa cell proliferation in vitro and xenograft tumor growth in vivo. Importantly, TRIM28 is upregulated in aggressive PCa and associated with elevated levels of TRIM24 and worse clinical outcome. TRIM24 and AR coactivated gene signature of SPOP-mutant PCa is similarly activated in human PCa with high TRIM28 expression. Taken together, this study provides a novel mechanism to broad TRIM24 protein stabilization and establishes TRIM28 as a promising therapeutic target.
| S-EPMC6258673 | biostudies-literature
Project description:In this study, proteomic profiling of TRIM24 interactome in conjunction with shRNA screening of TRIM24 top-interactors nominated that TRIM28 is indispensable for TRIM24 protein stability. We showed that TRIM28 stabilizes TRIM24 against SPOP-mediated ubiquitination and degradation. TRIM28 promotes TRIM24 and AR transcription activity, androgen-dependent and -independent PCa growth. In addition, we demonstrated that TRIM28 level in high in advanced PCa, which drives TRIM24/AR transcription activity in a similar manner to SPOP mutation, which implies that TRIM28 potentially dictates the therapeutic outcome of TRIM24-targeted therapy.
2018-10-05 | GSE108145 | GEO
Project description:In this study, proteomic profiling of TRIM24 interactome in conjunction with shRNA screening of TRIM24 top-interactors nominated that TRIM28 is indispensable for TRIM24 protein stability. We showed that TRIM28 stabilizes TRIM24 against SPOP-mediated ubiquitination and degradation. TRIM28 promotes TRIM24 and AR transcription activity, androgen-dependent and -independent PCa growth. In addition, we demonstrated that TRIM28 level in high in advanced PCa, which drives TRIM24/AR transcription activity in a similar manner to SPOP mutation, which implies that TRIM28 potentially dictates the therapeutic outcome of TRIM24-targeted therapy.
2018-10-05 | GSE108144 | GEO
Project description:TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression
| PRJNA422586 | ENA
Project description:TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression [microarray]
| PRJNA422592 | ENA
Project description:TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression [ChIP-seq]
| PRJNA422654 | ENA
Project description: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.
| S-EPMC6042370 | biostudies-literature
Project description:NANOG is an essential transcriptional factor for the maintenance of embryonic stem cells (ESCs) and cancer stem cells (CSCs) in prostate cancer (PCa). However, the regulation mechanism of NANOG protein stability in cancer progression is still elusive. Here, we report that NANOG is degraded by SPOP, a frequently mutated tumor suppressor of PCa. Cancer-associated mutations of SPOP or the mutation of NANOG at S68Y abrogates the SPOP-mediated NANOG degradation, leading to elevated PCa cancer stemness and poor prognosis. In addition, SPOP-mediated NANOG degradation is controlled by the AMPK-BRAF signal axis through the phosphorylation of NANOG at Ser68, which blocked the interaction between SPOP and NANOG. Thus, our study provides a regulation mechanism of PCa stemness controlled by phosphorylation-mediated NANOG stability, which helps to identify novel drug targets and improve therapeutic strategy for PCa.
| S-EPMC7523188 | biostudies-literature
Project description:The E3 ubiquitin ligase adaptor Speckle-type POZ protein (SPOP) plays an important tumour suppressor role in prostate cancers (PCa), with mutation rate up to 15%. However, how SPOP mutations regulate prostate tumorigenesis remains elusive. Here, we report the identification of cell division cycle associated 5 (CDCA5) as a SPOP substrate. We found that SPOP interacts with CDCA5 and promotes its polyubiquitin degradation in a degron-dependent manner. This effect was greatly impaired by introducing PCa associated SPOP mutations. Importantly, we found that CDCA5 was essential for PCa cells to survive and proliferate. CDCA5 depletion in PCa cells led to cessation of proliferation, G2M arrest, severe sister chromatid aggregation disturbance, and apoptosis. we also found that CDCA5 knockdown decreased the protein expression of p-GSK3β, increased the activity of caspase-3, caspase-9, and the Bax/Bcl-2 ratio. Besides, we confirmed that CDCA5 interrupted cancer cell behavior via the AKT pathway. In contrast, silencing SPOP or overexpressing CDCA5 increased cell proliferation. Consistently, depleting SPOP along with CDCA5, or overexpressing CDCA5 along with SPOP also caused the growth of cells repressed. Consistent with the functional role of CDCA5, the mRNA and protein levels of CDCA5 were significantly increased in PCa, compared to normal tissues, and its high expression was associated with more severe lymph node metastasis, higher Gleason score, and poorer prognosis. Together, our data showed that SPOP plays a crucial role in inhibiting tumorigenesis and partly achieved this by promoting the degradation of oncoprotein CDCA5.
| S-EPMC8435818 | biostudies-literature
Project description:The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (?ERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/?ERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.
| S-EPMC4575912 | biostudies-literature