Pancreatic b-cells are critical mediators of glucose homeostasis in the body, and proper cellular nutrient metabolism is critical to b-cell function. Several interacting signaling networks that uniquely control b-cell metabolism produce essential substrates and co-factors for catalytic reactions, including reactions that modify chromatin. Chromatin modifications, in turn, regulate gene expression. The reactions that modify chromatin are therefore well-positioned to adjust gene expression programs according to nutrient availability. It follows that dysregulation of nutrient metabolism in b-cells may impact chromatin state and gene expression through altering the availability of these substrates and co-factors. Metabolic disorders such as type 2 diabetes (T2D) can significantly alter metabolite levels in cells. This suggests that a driver of b-cell dysfunction during T2D may be the altered availability of substrates or co-factors necessary to maintain b-cell chromatin state. Induced changes in the b-cell chromatin modifications may then lead to dysregulation of gene expression, in turn contributing to the downward cascade of events that leads to the loss of functional b-cell mass, and loss of glucose homeostasis, that occurs in T2D.

Facility and ethical procedures were followed according to protocols approved by the University of British Columbia Animal Care Committee. All mice were maintained on a regular chow diet ad libitum and housed up to 5 mice per cage on a 12-hour light/dark cycle. Timed matings were used to determine embryonic stages and the morning of vaginal plug discovery was considered embryonic day 0.5 (E0.5). Previously generated Dpy30 flox/flox mice ( 22) were crossed to Neurog3-Cre driver mice ( 23) to obtain conditional deletion of Dpy30 exon 4 in endocrine progenitors. In all studies, knockout mice (Dpy30N; Neurog3-Cre; Dpy30 flox/flox ) were compared to Cre-negative littermate controls (Dpy30 flox/flox or Dpy30 flox/wt ). At noon on the day

Despite the amenability of early-stage prostate cancer to surgery and radiation therapy, locally advanced and metastatic prostate cancer is clinically problematic. Chemical castration is often used as a first-line therapy for advanced disease, but progression to the castration-resistant prostate cancer phase occurs with dependable frequency, largely through mutations to the androgen receptor (AR), aberrant AR signaling, and AR-independent mechanisms, among other causes. Semaphorin 3C (SEMA3C) is a secreted signaling protein that is essential for cardiac and neuronal development and has been shown to be regulated by the AR, to drive epithelial-to-mesenchymal transition and stem features in prostate cells, to activate receptor tyrosine kinases, and to promote cancer progression. Given that SEMA3C is linked to several key aspects of prostate cancer progression, we set out to explore SEMA3C inhibition by small molecules as a prospective cancer therapy. A homology-based SEMA3C protein structure was created, and its interaction with the neuropilin (NRP)-1 receptor was modeled to guide the development of the corresponding disrupting compounds. Experimental screening of 146 in silico‒identified molecules from the National Cancer Institute library led to the discovery of four promising candidates that effectively bind to SEMA3C, inhibit its association with NRP1, and attenuate prostate cancer growth. These findings provide proof of concept for the feasibility of inhibiting SEMA3C with small molecules as a therapeutic approach for prostate cancer.