Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.

Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer.

ISL-1 is induced in stomach mesenchyme in the presence of pancreatic epithelia.

BACKGROUND/PURPOSE: beta-Cell replacement offers a potential cure for type 1 diabetes mellitus in children. We have previously shown that stomach mesenchyme (SM) is competent to derive islet tissue by mesenchymal-to-epithelial transition (iMET). The aim of this study was to further characterize the developmental fate of this SM in the presence of pancreatic epithelia (PE) in SM/PE recombinants. The homeobox ISL-1 was examined in these recombinants because this gene is restricted to the dorsal pancreatic mesenchyme and endocrine cells in early pancreatic development. METHODS: Chick-quail recombinants of SM + PE (n = 15) and whole stomach controls (n = 8) were cultured for 7 days. In addition, organ blocks were examined after normal development at days 4 to 10 (n = 4 for each stage). Tissues were analyzed using immunochemistry against quail-specific antigen and ISL-1. RESULTS: Thirteen of 15 SM + PE recombinants expressed the ISL-1 protein in cells from SM origin. Nine of 15 of these recombinants showed iMET and coexpression of insulin, and ISL-1 was recorded. CONCLUSIONS: Pancreatic epithelium is able to reprogram SM to a more caudal pancreatic fate when cocultured. Islet tissue by mesenchymal-to-epithelial transition observed in recombinants showed coexpression of insulin and ISL-1. These experiments are important to identify the molecular mechanisms behind iMET for potential therapeutic use for treating children with diabetes.