![]() In this regard, tumor development is formally compared to Darwinian evolution in which a succession of genetic changes leads to the onset of hallmarks of cancer cells. Tumorigenesis is a dynamic process which takes place in several steps that drive the progressive transformation of normal human cells into their highly malignant counterparts. In this review, we discuss the role of the epigenetic readers in the regulation of cellular identity in physiological and tumorigenic contexts, and the putative translational breakthroughs in glioma treatment. ![]() Therefore, their altered expression in GBM and the therapeutic effectiveness of pharmacological inhibitors, observed in a wide range of cancers, including hematopoietic malignancies, neuroblastomas, breast cancer, and prostate cancer, have suggested BET proteins as promising targets for the treatment of GBM. Deregulation of BET expression leads to changes in transcriptome with consequent loss of cellular identity and proper functioning, the main driving-force of cancerogenesis. BETs belong to an evolutionarily maintained protein family, that regulates gene expression via recognizing acetylated lysine residues on histone and nonhistone chromatin factors. ![]() Among these, the chromatin readers bromodomain and extra-terminal domain (BET) proteins were found to be significantly overexpressed in GBM tissue rather than in the normal brain. The epigenetic landscape of GBM has been thoroughly explored and many epigenetic alterations, such as histone modification, DNA methylation, and chromatin remodeling, have been mechanistically linked to the biological features of the tumor. Genes and proteins that control epigenetic alterations have become potential novel therapeutic targets for tumors, particularly attractive due to the reversibility of epigenetic modifications. Recently, epigenetic therapy has gained increasing interest, consisting of the manipulation of the cancer epigenome through the targeting of epigenetic factors frequently deregulated in several type of malignancies. Therefore, it appears evident that there is a compelling need for novel and more effective treatment strategies. Moreover, resistant GBM cells are not easily accessible to chemo-therapeutic drugs due to the presence of the blood-brain-barrier (BBB) that prevents drugs from reaching the tumor. In detail, GBM recurrence arises from residual cells at the margin of the resection that rapidly acquire radio- and chemo-resistance during treatment and cannot be efficiently counteracted by any treatments. Altogether, these factors make inevitable relapses occurrence. ![]() GBM response to these therapeutic approaches is limited due to (1) the broad tumor capability to invade the surrounding brain tissue, that makes it unrealistic for surgery to remove all tumor cells (2) the presence of a sub-population of drug-resistant cells. Indeed, in the last 30 years a limited progress has been made in GBM treatment with current first-line standards-of-care involving maximal safe tumor resection with adjuvant temozolomide (TMZ)-based chemotherapy and radiotherapy. Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adult humans, characterized by a poor prognosis despite the existence of multimodal therapy. Primarily, “Reprogramming Therapy”, which is aimed at reverting the malignant phenotype, is now considered a promising strategy for GBM therapy. Therefore, the emerging roles of BET protein in glioblastoma onco-biology and the compelling demand for more effective therapeutic strategies suggest that BET family members could be promising targets for translational breakthroughs in glioblastoma treatment. Interestingly, epigenome dysregulation associated with loss of cellular identity and functions are emerging as crucial features of glioblastoma pathogenesis. Recently, new insights are emerging about the glioblastoma cellular origin, leading to the hypothesis that several putative mechanisms occur during gliomagenesis. Glioblastoma is the most aggressive form of glioma, characterized by a very poor prognosis despite the application of a multimodal therapy. Transcriptome handling ability of BET proteins suggests a key role in the modulation of cell plasticity, both in fate decision and in lineage commitment during embryonic development and in pathogenic conditions, including cancerogenesis. BET proteins are a family of multifunctional epigenetic readers, mainly involved in transcriptional regulation through chromatin modelling.
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