The cancer epigenome : towards epigenetic therapy

Abstract

Epigenetic gene silencing occurs in many important biological processes including differentiation, senescence and imprinting. In most cases, epigenetic silencing is orchestrated by an intricate interplay between DNA methylation, histone modifications and nucleosome remodeling that act in concert to provide transcriptional repression. Epigenetic gene silencing is deregulated in cancer, often leading to inactivation of genes that control key regulatory pathways in the cancer cell, which include many tumor suppressor genes (TSGs). The enzymes involved in epigenetic silencing of TSGs are often deregulated in cancer. In support of this notion, the recent cancer genome analyzes have identified an impressive and still increasing number of epigenetic enzymes to be subject to mutations in many types of cancer. Epigenetic modifications are reversible, making the enzymes responsible for establishing these modifications promising targets for therapeutic intervention

This notion together with the recognition that epigenetic enzymes are frequently deregulated in cancer has fueled the development of inhibitors of epigenetic enzymes. The usefulness of epigenetic therapy in cancer treatment has been clearly validated by the therapeutic successes of DNA methyl transferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) in some hematological malignancies.

The combination of DNMTi and HDACi in cancer therapy is being tested in clinical trials, given the ability of these agents to more effectively reactivate silenced TSGs. Moreover, this combination therapy may also compensate for lack of potency and prevent dose-related drug toxicities that can occur with these agents as monotherapy. Indeed, the combination of DNMTi and HDACi appears to induce more robust clinical responses in several early phase clinical trials. One potential complication in the use of the current generation of HDACi and DNMTi in cancer therapy is their limited target selectivity and off-target effects. Consequently, current HDACi and DNMTi induce global effects on gene expressionthat control many cellular pathways that can be either supporting or inhibiting tumor growth, which might explain the heterogeneous clinical responses of tumors to these agents . As such, effective epigenetic therapy with these agents may benefit from identifying the relevant drug targets within these larger enzyme families to allow the development of more selective inhibitors. Another approach would be to develop novel agents that can selectively restore expression of epigenetically silenced TSGs while avoiding global gene activation and off-target effects. However, for most of these epimutated TSGs we have not identified the enzymes involved and consequently do not know the relevant drug targets.

The findings of this thesis address many of the issues described above and may therefore have important implications for epigenetic therapy in treatment of cancer. We discover epigenetic regulators of key biological processes including DNA repair, cell cycle, senescence and tissue remodeling that are frequently deregulated in cancer. We elucidate the molecular mechanism for the synergy between HDACi and DNMTi in reactivation of silenced TSGs and identify the relevant targets of currently used HDACi in TSG reactivation. Moreover, we identify the nucleosome remodeler CHD4 as a novel and potentially drug-able target in cancer therapy. Finally, we describe a pharmacokinetic factor that may determine responsiveness to epigenetic therapy with the currently used DNMTi decitabine in breast cancer.