The E3 ubiquitin ligase adaptor speckle-type POZ protein (SPOP) is frequently dysregulated in prostate adenocarcinoma (PC), via either somatic mutations or mRNA downregulation, suggesting an ...important tumour suppressor function. To examine its physiologic role in the prostate epithelium in vivo, we generated mice with prostate-specific biallelic ablation of Spop. These mice exhibited increased prostate mass, prostate epithelial cell proliferation, and expression of c-MYC protein compared to littermate controls, and eventually developed prostatic intraepithelial neoplasia (PIN). We found that SPOP
can physically interact with c-MYC protein and, upon exogenous expression in vitro, can promote c-MYC ubiquitination and degradation. This effect was attenuated in PC cells by introducing PC-associated SPOP mutants or upon knockdown of SPOP via short-hairpin-RNA, suggesting that SPOP inactivation directly increases c-MYC protein levels. Gene Set Enrichment Analysis revealed enrichment of Myc-induced genes in transcriptomic signatures associated with SPOP
. Likewise, we observed strong inverse correlation between c-MYC activity and SPOP mRNA levels in two independent PC patient cohorts. The core SPOP
;MYC
transcriptomic response, defined by the overlap between the SPOP
and c-MYC transcriptomic programmes, was also associated with inferior clinical outcome in human PCs. Finally, the organoid-forming capacity of Spop-null murine prostate cells was more sensitive to c-MYC inhibition than that of Spop-WT cells, suggesting that c-MYC upregulation functionally contributes to the proliferative phenotype of Spop knock-out prostates. Taken together, our data highlight SPOP as an important regulator of luminal epithelial cell proliferation and c-MYC expression in prostate physiology, identify c-MYC as a novel bona fide SPOP substrate, and help explain the frequent inactivation of SPOP in human PC. We propose SPOP
-induced stabilization of c-MYC protein as a novel mechanism that can increase total c-MYC levels in PC cells, in addition to amplification of c-MYC locus.
Genome rearrangements are important in pathology and evolution. The thesis of this review is that the genome is in peril when replication forks stall, and stalled forks are normally rescued by ...error-free mechanisms. Failure of error-free mechanisms results in large-scale chromosome changes called gross chromosomal rearrangements, GCRs, by the aficionados. In this review we discuss five error-free mechanisms a replication fork may use to overcome blockage, mechanisms that are still poorly understood. We then speculate on how genome rearrangements may occur when such mechanisms fail. Replication fork recovery failure may be an important feature of the oncogenic process. (Feedback to the authors on topics discussed herein is welcome.)
Purpose. The majority of resistance to outflow of aqueous humor resides at or near the inner wall of Schlemm's canal (SC). Transmembrane proteins that contribute to the generation of resistance to ...aqueous outflow likely participate in junctional complexes between SC cells. The purpose of the present study was to examine the expression of cadherins in SC cells that play a significant role in adherens junction complexes that control permeability of vascular endothelia. Methods. Identification of cadherin subtype mRNAs was examined by hybridization screening of three different SC cDNA libraries and by polymerase chain reaction analysis with degenerate primers. Expression of endothelial adherens proteins, vascular endothelial (VE)-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM-1), was examined by western blot analyses of whole cell lysates prepared from SC and trabecular meshwork cells and by immunofluorescence microscopy of frozen sections of human anterior chambers. As controls, bovine retinal, bovine aortic, human umbilical vein and human iliac vein endothelial cells were examined for VE-cadherin expression. Results. Screens of SC cDNAs revealed abundant expression of N-cadherin and VE-cadherin. Expression of VE-cadherin protein was identified in both inner and outer wall SC cells, appropriately localized to SC intercellular borders and appeared as a single band of ~130 kDa by western blot analysis. Specific labeling of PECAM-1 was similar to VE-cadherin and appeared as a single band of ~130 kDa by western blot analysis. Conclusions. VE-cadherin and PECAM-1 expression in SC suggests that SC cells are vascular in origin and contain adherens protein likely involved in restricting fluid flow across the inner wall of SC.
Based on pioneering work by Huggins, Hodges and others, hormonal therapies have been established as an effective approach for advanced prostate cancer (PC) for the past eight decades. However, it ...quickly became evident that androgen deprivation therapy (ADT) via surgical or medical castration accomplishes inadequate inhibition of the androgen receptor (AR) axis, with clinical resistance inevitably emerging due to adrenal and intratumoral sources of androgens and other mechanisms. Early efforts to augment ADT by adding adrenal-targeting agents (aminoglutethimide, ketoconazole) or AR antagonists (flutamide, bicalutamide, nilutamide, cyproterone) failed to achieve overall survival (OS) benefits, although they did exhibit some evidence of limited clinical activity. More recently, four new androgen receptor signaling inhibitors (ARSIs) successfully entered clinical practice. Specifically, the CYP17 inhibitor abiraterone acetate and the second generation AR antagonists (enzalutamide, apalutamide and darolutamide) achieved OS benefits for PC patients, confirmed the importance of reactivated AR signaling in castration-resistant PC and validated important concepts that had been proposed in the field several decades ago but had remained so far unproven, including adrenal-targeted therapy and combined androgen blockade. The past decade has seen steady advances toward more comprehensive AR axis targeting. Now the question is raised whether we have accomplished the maximum AR axis inhibition possible or there is still room for improvement. This review, marking the 80-year anniversary of ADT and 10-year anniversary of successful ARSIs, examines their current clinical use and discusses future directions, in particular combination regimens, to maximize their efficacy, delay emergence of resistance and improve patient outcomes.
Androgen receptor signaling is critical for prostate adenocarcinoma, even after androgen deprivation therapy. Persistence of intratumoral androgens has been found in castration-resistant prostate ...cancer and attributed to increased in situ synthesis. Recently, Sharifi and colleagues reported an additional mechanism that can enhance local androgenic exposure: downregulation of an androgen-inactivating enzyme.
The largest US cancer health disparity exists in prostate cancer, with Black men having more than a two-fold increased risk of dying from prostate cancer compared to all other races. This disparity ...is a result of a complex network of factors including socioeconomic status (SES), environmental exposures, and genetics/biology. Inequity in the US healthcare system has emerged as a major driver of disparity in prostate cancer outcomes and has raised concerns that the actual incidence rates may be higher than current estimates. However, emerging studies argue that equalizing healthcare access will not fully eliminate racial health disparities and highlight the important role of biology. Significant differences have been observed in prostate cancer biology between ancestral groups that may contribute to prostate cancer health disparities. Notably, relative to White men, Black men with prostate cancer exhibit increased androgen receptor signaling, genomic instability, metabolic dysregulation, and inflammatory and cytokine signaling. Immediate actions are needed to increase multi-center, interdisciplinary research to bridge the gap between social and biological determinants of prostate cancer health disparities.
•Black men are 2.14 times more likely to die from prostate cancer compared to White men.•Equalizing access-to-quality-care is unlikely to fully eliminate racial health disparities.•Significant differences have been observed in prostate cancer biology among various ancestral groups.•Interdisciplinary research is needed to bridge the gap between social and biological factors.•Increasing racial diversity in preclinical models and clinical trials is critically needed.
Eukaryotes are constantly fine-tuning their gene expression programs in response to the demands of the environment and the availability of nutrients. Such dynamic regulation of the genome ...necessitates versatile chromatin architecture. Rapid changes in transcript levels are brought about via a wide range of post-translational modifications of the histone proteins that control chromatin structure. Many enzymes responsible for these modifications have been identified and they require various metabolic cofactors or substrates for their activity. Herein, we highlight recent developments that have begun to reveal particular cellular metabolites that might in fact be underappreciated regulators of gene expression through their ability to modulate particular histone modifications.
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