Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein

The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention

Shifts in bacterial community composition associated with increased carbon cycling in a mosaic of phytoplankton blooms

Marine microbes have a pivotal role in the marine biogeochemical cycle of carbon, because they regulate the turnover of dissolved organic matter (DOM), one of the largest carbon reservoirs on Earth. Microbial communities and DOM are both highly diverse components of the ocean system, yet the role of microbial diversity for carbon processing remains thus far poorly understood. We report here results from an exploration of a mosaic of phytoplankton blooms induced by large-scale natural iron fertilization in the Southern Ocean. We show that in this unique ecosystem where concentrations of DOM are lowest in the global ocean, a patchwork of blooms is associated with diverse and distinct bacterial communities. By using on-board continuous cultures, we identify preferences in the degradation of DOM of different reactivity for taxa associated with contrasting blooms. We used the spatial and temporal variability provided by this natural laboratory to demonstrate that the magnitude of bacterial production is linked to the extent of compositional changes. Our results suggest that partitioning of the DOM resource could be a mechanism that structures bacterial communities with a positive feedback on carbon cycling. Our study, focused on bacterial carbon processing, highlights the potential role of diversity as a driving force for the cycling of biogeochemical elements