Divergent androgen regulation of unfolded protein response pathways drives prostate cancer

The unfolded protein response (UPR) is a homeostatic mechanism to maintain endoplasmic reticulum (ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive prostate cancer (PCa) growth, they may affect UPR pathways. Here, we show that the canonical UPR pathways are directly and divergently regulated by androgens in PCa cells, through the androgen receptor (AR), which is critical for PCa survival. AR bound to gene regulatory sites and activated the IRE1α branch, but simultaneously inhibited PERK signaling. Inhibition of the IRE1α arm profoundly reduced PCa cell growth in vitro as well as tumor formation in preclinical models of PCa in vivo. Consistently, AR and UPR gene expression were correlated in human PCa, and spliced XBP-1 expression was significantly upregulated in cancer compared with normal prostate. These data establish a genetic switch orchestrated by AR that divergently regulates the UPR pathways and suggest that targeting IRE1α signaling may have therapeutic utility in PCa.

HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies.

Climate drives temporal replacement and nested‐resultant richness patterns of Scottish coastal vegetation

Beta diversity quantifies spatial and/or temporal variation in species composition. It is comprised of two distinct components, species replacement and nestedness, which derive from opposing ecological processes. Using Scotland as a case study and a β-diversity partitioning framework, we investigate temporal replacement and nestedness patterns of coastal grassland species over a 34-yr time period. We aim to 1) understand the influence of two potentially pivotal processes (climate and land-use changes) on landscape-scale (5 × 5 km) temporal replacement and nestedness patterns, and 2) investigate whether patterns from one β-diversity component can mask observable patterns in the other.

We summarised key aspects of climate driven macro-ecological variation as measures of variance, long-term trends, between-year similarity and extremes, for three important climatic predictors (minimum temperature, water-balance and growing degree-days). Shifts in landscape-scale heterogeneity, a proxy of land-use change, was summarised as a spatial multiple-site dissimilarity measure. Together, these climatic and spatial predictors were used in a multi-model inference framework to gauge the relative contribution of each on temporal replacement and nestedness patterns.

Temporal β-diversity patterns were reasonably well explained by climate change but weakly explained by changes in landscape-scale heterogeneity. Climate was shown to have a greater influence on temporal nestedness than replacement patterns over our study period, linking nestedness patterns, as a result of imbalanced gains and losses, to climatic warming and extremes respectively. Important climatic predictors (i.e. growing degree-days) of temporal β-diversity were also identified, and contrasting patterns between the two β-diversity components revealed.

Results suggest climate influences plant species recruitment and establishment processes of Scotland's coastal grasslands, and while species extinctions take time, they are likely to be facilitated by climatic perturbations. Our findings also highlight the importance of distinguishing between different components of β-diversity, disentangling contrasting patterns than can mask one another.