Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent explosion in our knowledge of how chromatin organization modulates gene transcription has highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes--in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing--affect virtually every step in tumor progression. Intriguingly, methylation patterns are severely altered in tumors, with an overall hypomethylation of the genome and hypermethylation of islands of CpGs clusters within specific DNA regions. Though overexpression of DNA methyltransferases (DNMTs) has been proposed to be a mechanism for aberrant genome methylation, it does not explain the specific regional hypermethylation in cancer cells. We have analyzed the role of chromatin modifying activities in cell transformation using acute promyelocytic leukemia as a model system. This disease is caused by expression of the PML-RARalpha fusion protein, thus offering the opportunity of studying the mechanisms of leukemogenesis through molecular investigation of the activity of the directly transforming protein. Recent evidence suggests that PML-RARalpha as well as other leukemia-associated fusion proteins induce changes in the chromatin structure. Specifically, aberrant recruitment of different chromatin modifying enzymes to specific promoters induces DNA hypermethylation and heterochromatin formation, which consequentially leads to the transcriptional silencing of that genes. Importantly, these epigenetic modifications were found to contribute to the leukemogenic potential of PML-RARalpha. These observations suggest that epigenetic alterations could actively contribute to the development of APL and other hyperproliferative diseases.
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PMID:Epigenetic gene silencing in acute promyelocytic leukemia. 1531 23

In recent years the study of chemical modifications to chromatin and their effects on cellular processes has become increasingly important in the field of cancer research. Disruptions to the normal epigenetic pattern of the cell can serve as biomarkers and are important determinants of cancer progression. Accordingly, drugs that inhibit the enzymes responsible for modulating these epigenetic markers, in particular histone deacetylases, are the focus of intense research and development. In this chapter we provide an overview of class I and II histone deacetylases as well as a guide to the diverse types of histone deacetylase inhibitors and their activities in the context of APL. We also discuss the rationale for the use of histone deacetylase inhibitors in combination therapy for the treatment of cancer and the current status of clinical trials.
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PMID:Histone deacetylase inhibitors in APL and beyond. 1721 44

Aberrant activation of epithelial-mesenchymal transition (EMT) in carcinoma cells contributes to increased migration and invasion, metastasis, drug resistance, and tumor-initiating capacity. EMT is not always a binary process; rather, cells may exhibit a hybrid epithelial/mesenchymal (E/M) phenotype. ZEB1-a key transcription factor driving EMT-can both induce and maintain a mesenchymal phenotype. Recent studies have identified two novel autocrine feedback loops utilizing epithelial splicing regulatory protein 1 (ESRP1), hyaluronic acid synthase 2 (HAS2), and CD44 which maintain high levels of ZEB1. However, how the crosstalk between these feedback loops alters the dynamics of epithelial-hybrid-mesenchymal transition remains elusive. Here, using an integrated theoretical-experimental framework, we identify that these feedback loops can enable cells to stably maintain a hybrid E/M phenotype. Moreover, computational analysis identifies the regulation of ESRP1 as a crucial node, a prediction that is validated by experiments showing that knockdown of ESRP1 in stable hybrid E/M H1975 cells drives EMT. Finally, in multiple breast cancer datasets, high levels of ESRP1, ESRP1/HAS2, and ESRP1/ZEB1 correlate with poor prognosis, supporting the relevance of ZEB1/ESRP1 and ZEB1/HAS2 axes in tumor progression. Together, our results unravel how these interconnected feedback loops act in concert to regulate ZEB1 levels and to drive the dynamics of epithelial-hybrid-mesenchymal transition.
APL Bioeng 2018 Sep
PMID:Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer. 3106 17