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TP63, a member of the p53 gene family, can be expressed as six different protein isoforms. ∆Np63α is the predominantly expressed p63 isoform in squamous epithelia and is restricted to cells with proliferative potential while it is downregulated in cells undergoing terminal differentiation. ∆Np63α plays a critical role in the morphogenesis of organs/tissues developing by epithelial-mesenchimal interactions such as the epidermis, teeth, hair and glands. Herein, we present evidences that the Y box-binding protein-1 (YB-1), a member of the cold shock domain superfamily of proteins, interacts with ∆Np63α but not with the smaller ∆Np63γ isoform. YB-1 is a transcriptional/translational factor involved in cell proliferation, migration and transformation but the molecular mechanisms governing the involvement of YB-1 in these processes are still unclear.YB-1 shuttles between the nucleus and cytoplasm playing different and even conflicting functions according to its sub-cellular localization. We present data showing that enforced expression of ∆Np63α induces YB-1 nuclear localization and accumulation. In the nuclear compartment ∆Np63α and YB-1 activates the expression of the catalytic subunit of the PI3K kinase (PI3KCA) thereby inducing Akt1 phosphorylation and activation of a pro-survival pathway. Furthermore, our data suggest a role for ∆Np63α in the control of cell motility and adhesion through interaction with YB-1. We also present data showing that ∆Np63α and YB1 colocalize in proliferative cells of epithelia. Our data implicate the existence of a ∆Np63α-dependent mechanism governing cell proliferation and migration through the physical association between ∆Np63α and YB-1, a newly isolated p63 molecular partner

Background The dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival. However, its role in leukemia is still unclear. Methods We exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIP-seq data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype. Results We found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34+ cells. Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly, sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression. Conclusions Our results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML.

[Image: see text] Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit 6a. We identified compound 6j as the most potent and selective hHDAC6 inhibitor of the series. Biological investigation of compounds 6b, 6h, and 6j demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. 6j induced HDAC6-dependent pSTAT3 inhibition.

The ubiquitin proteasome system (UPS) is the main cellular degradation machinery designed for controlling turnover of critical proteins involved in cancer pathogenesis, including hematological malignancies. UPS plays a functional role in regulating turnover of key proteins involved in cell cycle arrest, apoptosis and terminal differentiation. When deregulated, it leads to several disorders, including cancer. Several studies indicate that, in some subtypes of human hematological neoplasms such as multiple myeloma and Burkitt’s lymphoma, abnormalities in the UPS made it an attractive therapeutic target due to pro-cancer activity. In this review, we discuss the aberrant role of UPS evaluating its impact in hematological malignancies. Finally, we also review the most promising therapeutic approaches to target UPS as powerful strategies to improve treatment of blood cancers.

Polycomb group (PcG) proteins regulate transcription, playing a key role in stemness and differentiation. Deregulation of PcG members is known to be involved in cancer pathogenesis. Emerging evidence suggests that CBX2, a member of the PcG protein family, is overexpressed in several human tumors, correlating with lower overall survival. Unraveling the mechanisms regulating CBX2 expression may thus provide a promising new target for anticancer strategies. Here we show that the HDAC inhibitor SAHA regulates CBX2 stability via a SUMO-triggered ubiquitin-mediated pathway in leukemia. We identify CBX4 and RNF4 as the E3 SUMO and E3 ubiquitin ligase, respectively, and describe the specific molecular mechanism regulating CBX2 protein stability. Finally, we show that CBX2-depleted leukemic cells display impaired proliferation, underscoring its critical role in regulating leukemia cell tumorogenicity. Our results show that SAHA affects CBX2 stability, revealing a potential SAHA-mediated anti-leukemic activity though SUMO2/3 pathway.

Purpose This study aims to analyze whether and how a set of financial ratios calculated on the basis of financial statement information would allow auditors of Italian local governments (LGs) to get an indication of LGs’ financial distress risk and, hence, to support politicians and managers in promptly detecting financial distress. Design/methodology/approach A model comprising a set of financial indicators that would distinguish distressed from not distressed LGs through a logistic regression approach has been estimated and applied to Italian LGs. The model is built on the basis of information pertaining to 44 distressed and 53 not distressed LGs for up to five years prior to bankruptcy and covers the period 2003-2012. Findings The model reveals that the percentage of personnel expenses over revenues, the turnover ratio of short-term liabilities over current revenues and the reliance on subsidies (calculated as subsidies per capita) are factors discriminating non-distressed LGs from the distressed ones. Practical implications The model could have political and practical implications. The possible use of this model as a complementary tool in auditing activities might be helpful for auditors in detecting financial distress promptly, thus potentially enabling politicians and managers to search for different ways to manage public resources to avoid the detrimental consequences related to the declaration of distress. Originality/value This model, contrary to existing models that use accrual accounting data, is applicable to LGs that adopt a modified cash accounting basis.

Glioblastoma (GBM), a high-grade glioma (WHO grade IV), is the most aggressive form of brain cancer. Available treatment options for GBM involve a combination of surgery, radiation and chemotherapy but result in a poor survival outcome. GBM is a high-vascularized tumor and antiangiogenic drugs are widely used in GBM therapy as adjuvants to control abnormal vasculature. Vasculogenic mimicry occurs in GBM as an alternative vascularization mechanism, providing a means whereby GBM can escape anti-angiogenic therapies. Here, using an in vitro tube formation assay on Matrigel&reg, we evaluated the ability of different histone deacetylase inhibitors (HDACis) to interfere with vasculogenic mimicry. We found that vorinostat (SAHA) and MC1568 inhibit tube formation by rat glioma C6 cells. Moreover, at sublethal doses for GBM cells, SAHA, trichostatin A (TSA), entinostat (MS275), and MC1568 significantly decrease tube formation by U87MG and by patient-derived human GBM cancer stem cells (CSCs). The reduced migration and invasion of HDACis-treated U87 cells, at least in part, may account for the inhibition of tube formation. In conclusion, our results indicate that HDACis are promising candidates for blocking vascular mimicry in GBM.

Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer cells, which are unable to differentiate. Although genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared with CD34+ cells. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOCS3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.