Finally, we showed that cells formed tumors when re-introduced into mice, providing an authentic in vitro-in vivo preclinical model of a subtype of prostate cancer with a hypermutator phenotype and an SPOP mutation.
SPOP was found to be strongly down-regulated in PCa (median=0.24; range=0.04-9.98) and its expression was associated with both, biochemical (p=0.003) and clinical progression free survival (p=0.023), the very low SPOP expression levels being associated to the worst prognosis.
The aim of this study was to compare the frequency of ERG rearrangement, PTEN deletion, SPINK1 overexpression, and SPOP mutation in prostate cancer in African American and Caucasian men.
This study reveals novel molecular events underlying the regulation of DDIT3 protein homeostasis and provides insight in understanding the relationship between SPOP mutations and ER stress dysregulation in prostate cancer.
This study identifies AR as a bona fide substrate of SPOP and elucidates a role of SPOP mutations in prostate cancer, thus implying the importance of this pathway in resistance to antiandrogen therapy of prostate cancer.
Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein.
We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions.
Using next-generation sequencing to analyze the mutations in PC, the main molecular PC subtypes were identified, which depended on the presence of fusion genes and FOXA1, CHD1, and SPOP point mutations; other driver mutations responsible for the progression of PC subclones were also characterized.
Our data show that resistance to BET inhibitors in SPOP-mutant prostate cancer can be overcome by combination with AKT inhibitors and further support the evaluation of SPOP mutations as biomarkers to guide BET-inhibitor-oriented therapy in patients with prostate cancer.
In summary, PRISM-SRM enables multiplexed, isoform-specific detection of mutant SPOP proteins in cell lysates, providing significant potential in biomarker development for prostate cancer.
More importantly, our results also provide a molecular basis for using combination with BET inhibitors and other inhibitors to treat prostate cancer patients with SPOP mutations.
Here, the authors show that a non-coding polymorphic regulatory element at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone dependent DNA damage response.