Proteotoxic stress and cell death in cancer cells

To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed at restoring proteostasis, allowing cells to survive the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious, and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress, and this condition could be exploited from a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells

HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications

Controlling access to genomic information and maintaining its stability are key aspects of cell life. Histone acetylation is a reversible epigenetic modification that allows access to DNA and the assembly of protein complexes that regulate mainly transcription but also other activities. Enzymes known as histone deacetylases (HDACs) are involved in the removal of the acetyl-group or in some cases of small hydrophobic moieties from histones but also from the non-histone substrate. The main achievement of HDACs on histones is to repress transcription and promote the formation of more compact chromatin. There are 18 different HDACs encoded in the human genome. Here we will discuss HDAC4, a member of the class IIa family, and its possible contribution to cancer development

Genetic programs driving oncogenic transformation: Lessons from in vitro models

Cancer complexity relies on the intracellular pleiotropy of oncogenes/tumor suppressors and in the strong interplay between tumors and micro- and macro-environments. Here we followed a reductionist approach, by analyzing the transcriptional adaptations induced by three oncogenes (RAS, MYC, and HDAC4) in an isogenic transformation process. Common pathways, in place of common genes became dysregulated. From our analysis it emerges that, during the process of transformation, tumor cells cultured in vitro prime some signaling pathways suitable for coping with the blood supply restriction, metabolic adaptations, infiltration of immune cells, and for acquiring the morphological plasticity needed during the metastatic phase. Finally, we identified two signatures of genes commonly regulated by the three oncogenes that successfully predict the outcome of patients affected by different cancer types. These results emphasize that, in spite of the heterogeneous mutational burden among different cancers and even within the same tumor, some common hubs do exist. Their location, at the intersection of the various signaling pathways, makes a therapeutic approach exploitable

Class IIa HDACs repressive activities on MEF2-depedent transcription are associated with poor prognosis of ER⁺ breast tumors.

MEF2s transcription factors and class IIa HDACs compose a fundamental axis for several differentiation pathways. Functional relationships between this axis and cancer are largely unexplored. We have found that class IIa HDACs are heterogeneously expressed and display redundant activities in breast cancer cells. Applying gene set enrichment analysis to compare the expression profile of a list of putative MEF2 target genes, we have discovered a correlation between the down-regulation of the MEF2 signature and the aggressiveness of ER(+) breast tumors. Kaplan-Meier analysis in ER(+) breast tumors evidenced an association between increased class IIa HDACs expression and reduced survival. The important role of the MEF2-HDAC axis in ER(+) breast cancer was confirmed in cultured cells. MCF7 ER(+) cells were susceptible to silencing of class IIa HDACs in terms of both MEF2-dependent transcription and apoptosis. Conversely, in ER(-) MDA-MB-231 cells, the repressive influence of class IIa HDACs was dispensable. Similarly, a class IIa HDAC-specific inhibitor preferentially promoted the up-regulation of several MEF2 target genes and apoptosis in ER(+) cell lines. The prosurvival function of class IIa HDACs could be explained by the repression of NR4A1/Nur77, a proapoptotic MEF2 target. In summary, our studies underscore a contribution of class IIa HDACs to aggressiveness of ER(+) tumors

A regulative epigenetic circuit supervised by HDAC7 represses IGFBP6 and IGFBP7 expression to sustain mammary stemness

Background: In the breast, the pleiotropic epigenetic regulator HDAC7 can influence stemness. Materials & Methods: The authors used MCF10 cells knocked-out for HDAC7 to explore the contribution of HDAC7 to IGF1 signaling. Results: HDAC7 buffers H3K27ac levels at the IGFBP6 and IGFBP7 genomic loci and influences their expression. In this manner, HDAC7 can tune IGF1 signaling to sustain stemness. In HDAC7 knocked-out cells, RXRA promotes the upregulation of IGFBP6/7 mRNAs. By contrast, HDAC7 increases FABP5 expression, possibly through repression of miR-218. High levels of FABP5 can reduce the delivery of all-trans-retinoic acid to RXRA. Accordingly, the silencing of FABP5 increases IGFBP6 and IGFBP7 expression and reduces mammosphere generation. Conclusion: The authors propose that HDAC7 controls the uptake of all-trans-retinoic acid, thus influencing RXRA activity and IGF1 signaling

Different class IIa HDACs repressive complexes regulate specific epigenetic responses related to cell survival in leiomyosarcoma cells

Transcriptional networks supervising class IIa HDAC expression are poorly defined. Here we demonstrate that MEF2D is the key factor controlling HDAC9 transcription. This control, which is part of a negative feed-back loop during muscle differentiation, is hijacked in cancer. In leiomyosarcomas the MEF2D/HDAC9 vicious circuit sustains proliferation and cell survival, through the repression of the death receptor FAS. Comprehensive genome-wide studies demonstrate that HDAC4 and HDAC9 control different genetic programs and show both specific and common genomic binding sites. Although the number of MEF2-target genes commonly regulated is similar, only HDAC4 represses many additional genes that are not MEF2D targets. As expected, HDAC4-/- and HDAC9-/- cells increase H3K27ac levels around the TSS of the respective repressed genes. However, these genes rarely show binding of the HDACs at their promoters. Frequently HDAC4 and HDAC9 bind intergenic regions. We demonstrate that these regions, recognized by MEF2D/HDAC4/HDAC9 repressive complexes, show the features of active enhancers. In these regions HDAC4 and HDAC9 can differentially influence H3K27 acetylation. Our studies describe new layers of class IIa HDACs regulation, including a dominant positional effect, and can contribute to explain the pleiotropic actions of MEF2 TFs

Evolution models for mass transportation problems

We present a survey on several mass transportation problems, in which a given mass dynamically moves from an initial configuration to a final one. The approach we consider is the one introduced by Benamou and Brenier in [5], where a suitable cost functional $F(\rho,v)$, depending on the density $\rho$ and on the velocity $v$ (which fulfill the continuity equation), has to be minimized. Acting on the functional $F$ various forms of mass transportation problems can be modeled, as for instance those presenting congestion effects, occurring in traffic simulations and in crowd motions, or concentration effects, which give rise to branched structures.Comment: 16 pages, 14 figures; Milan J. Math., (2012

Synchronous oceanic spreading and continental rifting in West Antarctica

Magnetic anomalies associated with new ocean crust formation in the Adare Basin off north-western Ross Sea (43 – 26 Ma) can be traced directly into the Northern Basin that underlies the adjacent morphological continental shelf, implying a continuity in the emplacement of oceanic crust. Steep gravity gradients along the margins of the Northern Basin, particularly in the east, suggest that little extension and thinning of continental crust occurred before it ruptured and the new oceanic crust formed, unlike most other continental rifts and the Victoria Land Basin further south. A pre-existing weak crust and localisation of strain by strike slip faulting are proposed as the factors allowing the rapid rupture of continental crust