Proc Natl Acad Sci U S A
Z. Chen, D. Wu, J. M. Thomas-Ahner, C. Lu, P. Zhao, Q. Zhang, C. Geraghty, P. S. Yan, W. Hankey, B. Sunkel, X. Cheng, E. S. Antonarakis, Q. E. Wang, Z. Liu, T. H. Huang, V. X. Jin, S. K. Clinton, J. Luo, J. Huang and Q. Wang
Jun 26, 2018
The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7-driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7-driven prostate tumors.
https://www.ncbi.nlm.nih.gov/pubmed/29844167
Combinatorial Drug Discovery in Nanoliter Droplets
Proc Natl Acad Sci U S A
A. Kulesa, J. Kehe, J. E. Hurtado, P. Tawde and P. C. Blainey
Jun 26, 2018
Combinatorial drug treatment strategies perturb biological networks synergistically to achieve therapeutic effects and represent major opportunities to develop advanced treatments across a variety of human disease areas. However, the discovery of new combinatorial treatments is challenged by the sheer scale of combinatorial chemical space. Here, we report a high-throughput system for nanoliter-scale phenotypic screening that formulates a chemical library in nanoliter droplet emulsions and automates the construction of chemical combinations en masse using parallel droplet processing. We applied this system to predict synergy between more than 4,000 investigational and approved drugs and a panel of 10 antibiotics against Escherichia coli, a model gram-negative pathogen. We found a range of drugs not previously indicated for infectious disease that synergize with antibiotics. Our validated hits include drugs that synergize with the antibiotics vancomycin, erythromycin, and novobiocin, which are used against gram-positive bacteria but are not effective by themselves to resolve gram-negative infections.
https://www.ncbi.nlm.nih.gov/pubmed/29899149
Hoxb13 Mediates Ar-V7 Activity in Prostate Cancer
Proc Natl Acad Sci U S A
H. I. Navarro and A. S. Goldstein
Jun 26, 2018
https://www.ncbi.nlm.nih.gov/pubmed/29891672
On the Role of Sidechain Size and Charge in the Aggregation of Abeta42 with Familial Mutations
Proc Natl Acad Sci U S A
X. Yang, G. Meisl, B. Frohm, E. Thulin, T. P. J. Knowles and S. Linse
Jun 26, 2018
The aggregation of the amyloid-beta (Abeta) peptide is linked to the pathogenesis of Alzheimer's disease (AD). In particular, some point mutations within Abeta are associated with early-onset familial Alzheimer's disease. Here we set out to explore how the physical properties of the altered side chains, including their sizes and charges, affect the molecular mechanisms of aggregation. We focus on Abeta42 with familial mutations-A21G (Flemish), E22K (Italian), E22G (Arctic), E22Q (Dutch), and D23N (Iowa)-which lead to similar or identical pathology with sporadic AD or severe cerebral amyloid angiopathy. Through global kinetic analysis, we find that for the E22K, E22G, E22Q, and D23N mutations, the acceleration of the overall aggregation originates primarily from the modulation of the nucleation processes, in particular secondary nucleation on the surface of existing fibrils, whereas the elongation process is not significantly affected. Remarkably, the D23 position appears to be responsible for most of the charge effects during nucleation, while the size of the side chain at the E22 position plays a more significant role than its charge. Thus, we have developed a kinetic approach to determine the nature and the magnitude of the contribution of specific residues to the rate of individual steps of the aggregation reaction, through targeted mutations and variations in ionic strength. This strategy can help rationalize the effect of some disease-related mutations as well as yield insights into the mechanism of aggregation and the transition states of the wild-type protein.
https://www.ncbi.nlm.nih.gov/pubmed/29895690