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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].
Atypical Teratoid / Rhabdoid Tumors – AT/RT
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Michael C. Frühwald, Jaclyn A. Biegel, Susan N. Chi
Epigenetic targeting is currently one of the most active areas of research in drug development. The inhibition of enzymatic activities involved in epigenetic silencing by histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and enhancer of zeste homolog 2 (EZH2) is being tested in multiple active clinical trials. The antagonistic relationship between SWI/SNF and the polycomb repressive complex 2 (PRC2) plays a critical role in gene transcription and makes it an attractive target for therapy in AT/RT.114 EZH2 is critical for normal development and lineage-specific differentiation. Overexpression of EZH2 leads to the maintenance of a pluripotent state.115 Preclinical studies reported elevated expression of EZH2 in SMARCB1-deficient cells and demonstrated apoptosis in EZH2-depleted rhabdoid tumor cell lines.116 Further experimentation demonstrated upregulation of EZH2 following SMARCB1 loss. This was accompanied by widespread trimethylation of histone H3K27 and repression of p16INK4.117 Potent, selective EZH2 inhibitors have been developed. One of these, tazemetostat (EPZ-6438), is a selective orally bioavailable inhibitor of EZH2’s enzymatic activity.
Weaver Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Located on chromosome 7q36.1, the enhancer of zeste, drosophila, homolog 2 gene (EZH2) comprises multiple alternative transcripts, the longest of which has 20 exons and encodes a 751-amino-acid histone methyltransferase (EZH2) with a critical SET [su(var)3–9, enhancer of zeste, trithorax] domain, a pre-SET CXC domain, and two additional SANT (Sw13, Ada2, N-cor TFIIIB) domains. EZH2 constitutes the catalytic subunit of the polycomb-repressive complex 2 (PRC2), which also includes additional core components SUZ12 (suppressor of zeste 12) and EED (embryonic ectoderm development). As a highly conserved epigenetic modifying complex, PRC2 induces trimethylation of histone H3 at lysine 27 (resulting in H3K27me3), which serves as an epigenetic signal for chromatin condensation and transcriptional repression and contributes to the regulation of chondrocyte proliferation and hypertrophy in the growth plate [9]. Functional loss of any of the components (i.e., EZH2, SUZ12, and EED) compromises the enzymatic activity of PRC2 and subsequent reduction of H3K27me3, leading to transcriptional activation of loci to which H3K27me3 is bound [10–12].
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].
Preclinical pharmacokinetics and metabolism of MAK683, a clinical stage selective oral embryonic ectoderm development (EED) inhibitor for cancer treatment
Published in Xenobiotica, 2022
Ji Yue (Jeff) Zhang, Jiangwei Zhang, Michael Kiffe, Markus Walles, Yi Jin, Joachim Blanz, Jerôme Dayer, Arevalo Sanchez, Chunye Zhang, Lijun Zhang, Ying Huang, Counde Oyang
Histone modification is one of the key epigenetic mechanisms in regulating many fundamental cellular processes. Polycomb Repressive Complex 2 (PRC2) is a key transcriptional repressor that plays an essential role in regulating gene expression through its lysine methyltransferase activity on histone H3 lysine 27 (H3K27) (Xu et al. 2010; Margueron and Reinberg 2011). The functional core of PRC2 that essential to catalyse the methylation of H3K27 consists of one of the SET-domain-containing histone methyltransferases enhancer of zeste (EZH2 or EZH1), embryonic ectoderm development (EED), suppressor of zeste (SUZ12), and the CAF1 histone-binding proteins RBBP4 and RBBP7. Dysregulation of PRC2 is observed in multiple human cancers. The catalytic subunit EZH2 is overexpressed in a wide range of human cancers and is associated with cell proliferation and poor prognosis in patients (Varambally et al. 2002; McCabe and Creasy 2014; Kim and Roberts 2016). Moreover, gain-of-function mutations in EZH2 have been implicated in follicular lymphoma, diffuse large B cell lymphoma, parathyroid carcinoma, and melanoma, while functionally similar mutations in EZH1 have been reported in autonomous thyroid adenomas. These mutations increase the methyltransferase activity of PRC2 thereby increasing the level of H3K27me3 in cells and aberrantly repressing gene expression (Audia and Campbell 2016).
Targeting PRC2 for the treatment of cancer: an updated patent review (2016 - 2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Milly Dockerill, Clare Gregson, Daniel H. O’ Donovan
Polycomb repressive complex 2 (PRC2) is a multi-protein assembly which regulates gene silencing and chromatin remodeling via its methyltransferase activity, acting on lysine 27 of histone H3 (H3K27)[1]. Trimethylation of H3K27 serves as an epigenetic marker which promotes transcriptional silencing including the regulation of key developmental markers such as Hox genes[2]. PRC2 is found in the majority of eukaryotic organisms and the deletion of PRC2 components is embryonic lethal, underlining its essential role in development, stem cell differentiation and plasticity. The PRC2 complex includes at least three core proteins: one of either EZH1 or EZH2, EED and SUZ12 (Figure 1). Other proteins may also be incorporated depending on the variable composition of the complex; these changeable components include RbAp46/48, AEBP2 and Jarid2, among others [1,3].