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.

The quantification of the kinetic rates of RNA synthesis, processing, and degradation are largely based on the integrative analysis of total and nascent transcription, the latter being quantified through RNA metabolic labeling. We developed INSPEcT−, a computational method based on the mathematical modeling of premature and mature RNA expression that is able to quantify kinetic rates from steady-state or time course total RNA-seq data without requiring any information on nascent transcripts. Our approach outperforms available solutions, closely recapitulates the kinetic rates obtained through RNA metabolic labeling, improves the ability to detect changes in transcript half-lives, reduces the cost and complexity of the experiments, and can be adopted to study experimental conditions in which nascent transcription cannot be readily profiled. Finally, we applied INSPEcT− to the characterization of post-transcriptional regulation landscapes in dozens of physiological and disease conditions. This approach was included in the INSPEcT Bioconductor package, which can now unveil RNA dynamics from steady-state or time course data, with or without the profiling of nascent RNA.

Alteration of the chromatin orchestra seems to play a critical role in cancer. In recent years, in-depth studies of epigenetic machinery and its deregulation have led to the development and use of a wide range of modulatory molecules directed not only at chromatin enzymes (histone acetyltransferases, histone deacetylases, histone methyltransferases, histone demethylases and DNA methyltransferases) but also toward the emerging class of chromatin-associated proteins, so-called "histone readers." Chromatin modifiers are attractive therapeutic targets for the development of new cancer therapies. Many are currently approved by the US Food and Drug Administration and used to treat different malignancies. Specifically, inhibitors of DNA methyltransferases, such as azacitidine and decitabine, have been approved for the treatment of myelodysplastic syndrome, while inhibitors of histone deacetylases, including vorinostat and romidepsin, have been approved for cutaneous T-cell lymphoma. The bromodomain and extra-terminal inhibitors JQ1, IBET762 and IBET151 have performed extremely well in preclinical settings, suggesting that they may be promising molecules for the treatment of some type of tumors. This review focuses on epidrugs and their possible application, with particular emphasis on their mechanism of action as well as their present status in clinical and preclinical trials.

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®, 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.