◥ p27 binds and inhibits cyclin-CDK to arrest the cell cycle. p27 also regulates other processes including cell migration and development independent of its cyclin-dependent kinase (CDK) inhibitory action. p27 is an atypical tumor suppressor-deletion or mutational inactivation of the gene encoding p27, CDKN1B, is rare in human cancers. p27 is rarely fully lost in cancers because it can play both tumor suppressive and oncogenic roles. Until recently, the paradigm was that oncogenic deregulation results from either loss of growth restraint due to excess p27 proteolysis or from an oncogenic gain of function through PI3K-mediated C-terminal p27 phosphorylation, which disrupts the cytoskeleton to increase cell motility and metastasis. In cancers, C-terminal phosphorylation alters p27 protein-protein interactions and shifts p27 from CDK inhibitor to oncogene. Recent data indicate p27 regulates transcription and acts as a transcriptional coregulator of cJun. C-terminal p27 phosphorylation increases p27-cJun recruitment to and action on target genes to drive oncogenic pathways and repress differentiation programs. This review focuses on noncanonical, CDKindependent functions of p27 in migration, invasion, development, and gene expression, with emphasis on how transcriptional regulation by p27 illuminates its actions in cancer. A better understanding of how p27-associated transcriptional complexes are regulated might identify new therapeutic targets at the interface between differentiation and growth control. p27 Is a Ubiquitously Expressed Cell-Cycle InhibitorThe CDKN1B gene encodes p27, a cyclin-dependent kinase inhibitor (CDKi) of the kinase inhibitory protein (Kip) family. CDKis mediate cell-cycle inhibition. p27 is ubiquitously expressed and integrates mitogenic and growth inhibitory signals to govern normal cellcycle progression (1). p27 can inhibit the catalytic activity of cyclin D-, E-, A-, and B-CDK complexes (2) by interacting with both cyclin and CDK subunits via its N-terminal domain, which is conserved among Kip family members (p21, p27, and p57; refs. 1, 3).Antiproliferative and differentiation signals increase p27 to mediate cell-cycle arrest (2, 4-7). In normal cells, p27 levels are tightly regulated across the cell cycle. An increase in p27 by 2to 3-fold is sufficient to fully inhibit G 1 -S-phase cyclin-CDKs (8). In G 0 -phase and early G 1 -phase, p27 protein translation and stability are maximal (9-13) and it inhibits cyclin E-CDK2 (2, 14). A progressive decline in p27 is required to relieve the inhibition of cyclin E-and cyclin A-bound CDK2 and enable transcription of genes required for G 1 -to S-phase progression (1). Transient C-terminal p27 phosphorylation by PI3K/AKT in mid-G 1 -phase facilitates assembly and nuclear import of D-type cyclin-CDKs (15), permitting their activation (3,15,16). p27 proteolysis increases during G 1 -phase progression via a number of mechanisms. Phosphorylation at p27T187 by cyclin E or cyclin A-bound CDK2 triggers p27 turnover by promoting its polyubiquitination and de...
Briefly, our data shed more light on the role of CAFs through secretion of miRNAs within tumor microenvironment and propose novel therapeutic targets for esophageal and probably other cancer types.
Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical factor in learning and memory. Due to the important role of BDNF in synaptic function and plasticity, an in-house epigenetic library was screened against human neural progenitor cells (HNPCs) and WS1 human skin fibroblast cells using Cell-to-Ct assay kit to identify the small compounds capable of modulating the BDNF expression. In addition to two well-known hydroxamic acid-based histone deacetylase inhibitors (hb-HDACis), SAHA and TSA, several structurally similar HDAC inhibitors including SB-939, PCI-24781 and JNJ-26481585 with even higher impact on BDNF expression, were discovered in this study. Furthermore, by using well-developed immunohistochemistry assays, the selected compounds were also proved to have neurogenic potential improving the neurite outgrowth in HNPCs-derived neurons. In conclusion, we proved the neurogenic potential of several hb-HDACis, alongside their ability to enhance BDNF expression, which by modulating the neurogenesis and/or compensating for neuronal loss, could be propitious for treatment of neurological disorders.
Immunocore and AJE has unlicensed patents on keratin-14 as a biomarker in breast cancer and on the use of antibodies as anti-cancer therapeuticsResearch.
Supplementary Figure from DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer
<div>AbstractPurpose:<p>Although chemotherapies kill most cancer cells, stem cell–enriched survivors seed metastasis, particularly in triple-negative breast cancers (TNBC). TNBCs arise from and are enriched for tumor stem cells. Here, we tested if inhibition of DOT1L, an epigenetic regulator of normal tissue stem/progenitor populations, would target TNBC stem cells.</p>Experimental Design:<p>Effects of DOT1L inhibition by EPZ-5676 on stem cell properties were tested in three TNBC lines and four patient-derived xenograft (PDX) models and in isolated cancer stem cell (CSC)-enriched ALDH1<sup>+</sup> and ALDH1<sup>−</sup> populations. RNA sequencing compared DOT1L regulated pathways in ALDH1<sup>+</sup> and ALDH1<sup>−</sup> cells. To test if EPZ-5676 decreases CSC <i>in vivo</i>, limiting dilution assays of EPZ-5676/vehicle pretreated ALDH1<sup>+</sup> and ALDH1<sup>−</sup> cells were performed. Tumor latency, growth, and metastasis were evaluated. Antitumor activity was also tested in TNBC PDX and PDX-derived organoids.</p>Results:<p>ALDH1<sup>+</sup> TNBC cells exhibit higher DOT1L and H3K79me2 than ALDH1<sup>−</sup>. DOT1L maintains <i>MYC</i> expression and self-renewal in ALDH1<sup>+</sup> cells. Global profiling revealed that DOT1L governs oxidative phosphorylation, cMyc targets, DNA damage response, and WNT activation in ALDH1<sup>+</sup> but not in ALDH1<sup>−</sup> cells. EPZ-5676 reduced tumorspheres and ALDH1<sup>+</sup> cells <i>in vitro</i> and decreased tumor-initiating stem cells and metastasis in xenografts generated from ALDH1<sup>+</sup> but not ALDH1<sup>−</sup> populations <i>in vivo.</i> EPZ-5676 significantly reduced growth <i>in vivo</i> of one of two TNBC PDX tested and decreased clonogenic 3D growth of two other PDX-derived organoid cultures.</p>Conclusions:<p>DOT1L emerges as a key CSC regulator in TNBC. Present data support further clinical investigation of DOT1L inhibitors to target stem cell–enriched TNBC.</p></div>
Supplementary Data from DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer
Supplementary Figure from DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer
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