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PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alicja M. Gruszkaa, Myriam Alcalay
PML/RARa behaves as a potent repressor of the RA signalling pathway (Fig. 10.1). The traditional model postulated that PML/RARa acted as a constitutive transcriptional repressor that altered the normal RARa signalling in APL cells, as the chimeric protein is unable to respond to physiological fluctuations of RA [42]. The transcriptional repression was shown to be the consequence of greatly enhanced binding to the SMRT/NCoR co-repressors and HDACs [23]. PML/RARa homodimerises and binds to DNA at the RARE sites even in the absence of its normal heterodimeric partner RXR. The homodimerisation is thought to enhance the binding of the physiological RARa interactors. Simplistically, enhanced corepressors binding depends upon the fact that the homodimer harbours two co-repressor docking sites and not just one as in RXR/RARa heterodimer, leading to a change in stoichiometry of association of PML/RARa with co-repressors and chromatin modifiers [39]. However, in addition, the formation of homodimers leads to the creation of novel binding interfaces. Histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3 is one of the chimera-specific partners responsible for imposing a heterochromatin-like structure on target genes, thereby establishing permanent transcriptional silencing [9]. Similarly, polycomb repressive complex 2 (PRC2) represents another example of a new PML/RARa interactor. It has been found that PRC2 is recruited to tumour suppressor genes causing and maintaining their silencing during the initial steps of PML/RARa driven leukaemogenesis [57].
Epigenetic Reprogramming of Mammalian Primordial Germ Cells
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Sebastian Canovas, Susana M. Chuva de Sousa Lopes
In the sperm, the paternal genome is tightly wrapped around protamines even though specific regions remain packaged with histones (66,67). The protamines are rapidly exchanged by canonical histones in the zygote. At the 2-cell stadium, mice embryos activate their own genome (embryonic genome activation) and both the maternal and paternal X chromosomes are transiently active. However, at the 4-cell stage the paternal X chromosome is obligatory silenced in all cells (imprinted X inactivation), by a mechanism that is regulated by the long-non coding RNA Xist. This molecule is transcribed and binds in cis to the X chromosome to be silenced, first coating the region of the X chromosome close to its locus, known as the X inactivation center, and then spreading in both directions. Xist attracts the polycomb repressive complex 2 (PRC2), containing EZH2 and EED. There, EZH2 converts H3K27me2 to H3K27me3 silencing that X chromosome (Xi). Subsequently, Xi is maintained by incorporation of the histone variant macroH2A and gain of chromosome-wide DNA methylation (68,69).
Precision medicine in acute myeloid leukemia
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Histone methylome (HMT) is another major epigenetic determinant in gene expression and is frequently deregulated in AML, especially in MLL-rearranged leukemia (Tsai and So, 2017). The first HMT inhibitor targeting DOTL1, EPZ4777, and its second-generation derivative, EPZ5676, have been developed and tested for suppressing MLL leukemia (Daigle et al., 2011, 2013). Both compounds showed selective inhibitory effects on H3K79 methylation and cells bearing MLL fusions, leading to the first clinical trial of HMT inhibitors in AML. Protein arginine N-methyltransferase 1 (PRMT1) inhibitor AMI-408 targets H4R3 methyltransferase, leading to repression of MLL fusion targets (Cheung et al., 2016). Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors DZNep and UNC1999 target H3K27 methyltransferase, leading to derepression of polycomb targets (Xu et al., 2015; Zhou et al., 2011).
Novel chromobox 2 inhibitory peptide decreases tumor progression
Published in Expert Opinion on Therapeutic Targets, 2023
Lindsay W. Brubaker, Donald S. Backos, Vu T. Nguyen, Philip Reigan, Tomomi M Yamamoto, Elizabeth R. Woodruff, Ritsuko Iwanaga, Michael F. Wempe, Vijay Kumar, Christianne Persenaire, Zachary L. Watson, Benjamin G. Bitler
Polycomb Repressor Complex 1 and 2 (PRC1 and PRC2) are epigenetic complexes involved in chromatin-based gene regulation. Both PRC1 and PRC2 are essential for development and cellular differentiation. PRC1 specifically coordinates stemness and is critical in embryonic development [1,2]. The canonical PRC1 consists of four main subunits including Ring1A and Ring1B/2, chromobox (CBX 2,4,6,7, and 8), polycomb group ring finger protein (PCGF 1–6, PCGF4 is BMI1, PCGF2 is MEL18), and polyhomeotic-like protein (PHC 1, 2, and 3) [3]. It is understood that PRC1 activity is multifaceted, and its function is dependent on the complex composition. There are possibly greater than 60 different compositional profiles [4], and subunits of the PRC1 complex are aberrantly expressed in cancer and often serve an oncogenic role in driving cancer progression [5–7].
Role of bromodomain and extraterminal (BET) proteins in prostate cancer
Published in Expert Opinion on Investigational Drugs, 2023
Adel Mandl, Mark C. Markowski, Michael A. Carducci, Emmanuel S. Antonarakis
The lack of biomarkers predicting sensitivity to BET inhibitors limits their application in clinical practice. Thus, there is a need to identify PC subtypes that show the highest degree of growth inhibition and adequately stratify tumors into responders versus non-responders. Further research is needed to determine if the overexpression of individual BET family members influences sensitivity to BET inhibitors. Identifying PC types strongly dependent upon BET proteins for survival might be one way to identify those most sensitive to the inhibitors. Further understanding of BET protein-driven transcriptional regulation mechanisms will likely reveal vulnerabilities that could be exploited using BET inhibitors. Substantial evidence shows that BET inhibitors lead to c-MYC downregulation, suggesting that elevated levels of c-MYC could enhance sensitivity to BET inhibitors and serve as a predictive biomarker. Conversely, SPOP-mutant prostate cancer may be primarily resistant to BET inhibition, as might prostate cancers with constitutive activation of the PI3K-mTOR pathway. Furthermore, there is substantial evidence that changes to the epigenetic landscape mediated by Polycomb group proteins might influence responses to BET inhibitors [112,123]. Future work could provide insights into the potential use of the expression profiles of Polycomb group proteins as putative biomarkers.
Epigenetic regulation of T cell development
Published in International Reviews of Immunology, 2023
Avik Dutta, Harini Venkataganesh, Paul E. Love
Several reports suggest that polycomb group (PcG) proteins govern the H3K27 methylation mark [25] and that Polycomb repressor complex (PRC) maintains the repressive state. There are three groups of PRCs: PRC1, PRC2, and Polycomb Repressive-Deubiquitinase (PR-DUB) complex [26, 27]. Each group has individual ways of remodeling chromatin, contributing to the epigenetic repression of genes important for cell development and proliferation. The PRC1 complex, which consists of several proteins including BMI-1, Ring1, and HPH proteins, recognizes and trimethylates K27 of histone 3 (H3K27me3) and helps to maintain the repressive state. The PRC2 complex includes EZH1 (enhancer of zeste homolog 1), EZH2, EED and SUV12 and initiates early gene repression with the help of histone deacetylases (HDACs) and DNMTs [25]. The discovery of histone demethylase LSD1 (Lysine-specific histone demethylase 1 A; encoded by the KDM1A gene) advanced the field as previously it was thought that histone methylation is permanent. This discovery has contributed to a dynamic view of chromatin remodeling [23, 28]. LSD1 demethylates H3K4 and H3K9 and is found to be upregulated in many cancers including T cell acute lymphoblastic leukemia (T-ALL) [29]. Several reports have also shown that the histone H3 K27 demethylases, KDM6A (Utx) and KDM6B (Jmjd3), help to shape the chromatin architecture and regulate gene expression by removing repressive histone modifications [30].