Epigenetic Therapy: Histone Acetylation, DNA Methylation and Anti-Cancer Drug Discovery

Abstract

Histone proteins are subject to a diverse range of post-translational modifications which, along with DNA methylation, play a major role in controlling gene expression, cell division, survival and differentiation. Alterations in these chromatin modifications are thought to contribute to important human diseases including cancer. Inhibition of the enzymes that introduce and remove these chromatin modifications is proving an effective approach to cancer therapy and inhibitors of histone deacetylases and DNA methyltransferases have been approved for use in haematological malignancies. Here we provide a background to the biology of chromatin modifications and review some of the evidence validating histone deacetylases and DNA methyltransferases as targets for anti-cancer drug discovery. We then focus on two of the key issues in this field; the identification of novel inhibitors to overcome shortcomings of first generation agents and the potential role of histone deacetylase and DNA methyltransferase inhibitors in combination therapies for oncology. Finally, we highlight some of the challenges that will need to addressed to further progress the development of epigenetic-based therapies for cancer.

Epigenetic Modifications: Therapeutic Potential in Cancer

“…DNMT3A deletion may promote cancer progression, whereas DNMT3B deletion may inhibit oncogenesis by liberating previously silenced tumor-suppressor genes. DNMTs cooperate to silence genes and promote cell survival in at least some human cancers and overexpression of DNMT1/3A/3B is common in the lung, prostate and breast cancer and in many other malignancies (Ganesan et al 2009). Patients with DNMT3A-mutated AML have an inferior survival when treated with standard-dose anthracycline induction therapy (Sehgal et al 2015).…”

Histone deacetylase inhibition redistributes topoisomerase IIb from heterochromatin to euchromatin

“…Consequently, HDAC inhibitors (HDACIs) are undergoing trials as anticancer agents. [6][7][8][9] HDACIs alone exert an antiproliferative effect and promote apoptosis in cancer cell-line models, but in addition HDACIs have been shown to sensitize cells to the cytotoxic effects of other anticancer…”

Isoform-Selective HDAC Inhibition in Autoimmune DiseaseNicole L Regna1* and Christopher M Reilly2

“…HDAC inhibitors currently undergoing phase II clinical trials include Mocetinostat (MGCD0103), Entinostat (MS-275), Belinostat (PXD101), and Givinostat (ITF2357) for the treatment of various cancers [53]. CUDC-101, ACY-1215, CHR-2845, and CG200745 have begun phase I clinical trials for the treatments of cancer [54,55]. Dokamanovic et al provide a more extensive review of specific HDAC inhibitors currently undergoing clinical trials [15].…”