Abstract
p21cip1/waf1 is a central regulator of cell cycle control and survival. While mutations are rare, it is commonly dysregulated in several human cancers due to epigenetic mechanisms influencing its transcriptional control. These mechanisms include promoter hypermethylation as well as additional pathways such as histone acetylation or methylation. The epigenetic regulators include writers, such as DNA methyltransferases (DNMTs); histone acetyltransferases (HATs) and histone lysine methyltransferases; erasers, such as histone deacetylases (HDACs); histone lysine demethylases [e.g., the Lysine Demethylase (KDM) family]; DNA hydroxylases; readers, such as the methyl-CpG-binding proteins (MBPs); and bromodomain-containing proteins, including the bromo- and extraterminal domain (BET) family. We further discuss the roles that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play in the epigenetic control of p21cip1/waf1 expression and its function in human cancers.
Highlights
Regulation of gene function is essential to the coordination of cellular processes and tissue homeostasis
Another study showed that miR-370, miR-1180, and miR-1236 are downregulated in bladder carcinoma tissues, and their overexpression led to p21cip1/waf1 activation and inhibition of cancer
The downregulation of growth arrest specific transcript 5 (GAS5) results in the downregulation of YBX1, a transactivator of p21cip1/waf1 in prostate cancer, thereby decreasing p21cip1/waf1 expression [145]. These findings show a biological significance for the role of long noncoding RNAs (lncRNAs) and miRNAs in the deregulation of p21cip1/waf1 in cancer
Summary
Regulation of gene function is essential to the coordination of cellular processes and tissue homeostasis. Dysregulation of genes is commonly mediated by genetic events such as activating mutations (e.g., k-RAS, PI3K, EGFR), gene fusions (e.g., BCR-ABL, NTREK), or amplifications (e.g., FGFR) Besides these mechanisms, additional features “on top” of the genetic information, i.e., epigenetic modifications, are heavily involved in the orchestration of gene functions. An epigenetic signature is mediated by enzymes that alter DNA methylation or modifications of histones via methylation, acetylation, phosphorylation, ubiquitination, and various other mechanisms [5]. P21cip1/waf is a low-molecular-weight molecule (21 kDa) that inhibits cyclin-dependent kinases It is a key downstream target of p53 upon DNA damage and has multiple functions during cell cycle regulation, DNA repair, gene transcription, and apoptosis [8]. We will extend this discussion to epigenetic mechanisms, such as DNA or histone methylation, and their effects on p21caip1/waf in cancer cells
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