Emerging epigenetic targets and therapies in cancer medicine

Abstract

Abnormalities in the epigenetic regulation of chromatin structure and function can lead to aberrant gene expression and cancer development. Consequently, epigenetic therapies aim to restore normal chromatin modification patterns through the inhibition of various components of the epigenetic machinery. Histone deacetylase and DNA methyltransferase inhibitors represent the first putative epigenetic therapies; however, these agents have pleiotropic effects and it remains unclear how they lead to therapeutic responses. More recently, drugs that inhibit histone methyltransferases were developed, perhaps representing more specific agents. We review emerging epigenetic targets in cancer and present recent models of promising epigenetic therapies.

Significance: The use of DNA methyltransferase and histone deacetylase inhibitors in patients has validated the use of drugs targeted to epigenetic enzymes and strengthened the need for development of additional therapies. In this review, we summarize recently discovered epigenetic abnormalities, their implications for cancer, and the approaches taken for discovering small-molecule inhibitors targeting various properties of the epigenetic machinery.

Fig 1

(A) Recruitment of DOT1L via MLL fusion proteins enhances gene expression, which can be inhibited by targeting DOT1L activity or MLL-menin interaction. (B) Different genetic alterations affect H3K27 methylation.

Fig 2

(A) BRD4 interaction with acetylated histones activates gene expression. Small molecule inhibitors (JQ1 or I-BET) that bind BRD4, preventing this interaction, lead to repression of BRD4 transcriptional targets. (B) Inhibition of BCL6-SMRT complex interaction by BPI (BCL6 Peptide Inhibitor) decreases HDAC recruitment, increasing histone acetylation and activating gene expression.