Targeting epigenetics for cancer therapy

Abstract

Cancer can be identified as a chaotic cell state, which breaks the rules that govern growth and reproduction, with main characteristics such as uncontrolled division, invading other tissues, usurping resources, and eventually killing its host. It was once believed that cancer is caused by a progressive series of genetic aberrations, and certain mutations of genes, including oncogenes and tumor suppressor genes, have been identified as the cause of cancer. However, piling evidence suggests that epigenetic modifications working in concert with genetic mechanisms to regulate transcriptional activity are dysregulated in many diseases, including cancer. Cancer epigenetics explain a wide range of heritable changes in gene expression, which do not come from any alteration in DNA sequences. Aberrant DNA methylation, histone modifications, and expression of long non-coding RNAs (lncRNAs) are key epigenetic mechanisms associated with tumor initiation, cancer progression, and metastasis. Within the past decade, cancer epigenetics have enabled us to develop novel biomarkers and therapeutic target for many types of cancers. In this review, we will summarize the major epigenetic changes involved in cancer biology along with clinical and preclinical results developed as novel cancer therapeutics.

Keywords: Cancer epigenetics; DNA methylation; Epigenetic drugs; Histone modification.

Fig. 1

Graphic summary of epigenetic alterations involved in cancer and available drugs targeting epigenetic mechanisms. a Tumorigenesis through aberrant methylation of CpG islands. DNA methylation can be written by DNMTs (in blue), recognized by MBD proteins (in green) and erased by TET proteins (in red). Epigenetic drugs targeting DNMT1 are approved by the FDA. b Tumorigenesis through aberrant histone modifications. Writers of each histone modification such as histone lysine methyltransferase (KMT), histone acetyltransferase (HAT), ubiquitin E3 ligases (E3 lig), protein arginine methyltransferase (PRMT), kinase are shown in blue. Readers such as methyl-lysine binding protein, tudor domain protein, bromodomain and extra terminal domain family member (BRD) are shown in green. Erasers such as histone deacetylase (HDAC), histone lysine demethylase (KDM), and deubiquitinating enzyme (DUB), phosphatase are shown in red. Canonical histone is shown in blue and histone variants is shown in brown. KMT inhibitors, KDM1 inhibitors, BET inhibitors, HDAC inhibitors are either approved or under clinical trials. Apart from the targets shown here other possible epigenetic targets for drug development are also available. AC acetylation, ME methylation, Ub ubiquitination, P phosphorylation