Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors

Abstract

Introduction: Altered epigenetic map is frequently observed in cancer and recent investigations have demonstrated a pertinent role of epigenetic modifications in the response to many anticancer drugs including the DNA damaging agents. Topoisomerase I (Top I) is a well-known nuclear enzyme that is critical for DNA function and cell survival and its inhibition causes DNA strand breaks and cell cycle arrest. Inhibitors of human Top I have proven to be a prosperous chemotherapeutic treatment for a vast number of cancer patients. While the treatment is efficacious in many cases, resistance and altered cellular response remain major therapeutic issues.

Areas covered: This review highlights the evidence available till date on the influence of different epigenetic modifications on the response to Top I inhibitors as well as the implications of targeting epigenetic alterations for improving the efficacy and safety of Top I inhibitors.

Expert opinion: The field of epigenetic research is steadily growing. With its assistance, we could gain better understanding on how drug response and resistance work. Epigenetics can evolve as possible biomarkers and predictors of response to many medications including Top I inhibitors, and could have significant clinical implications that necessitate deeper attention.HIGHLIGHTSEpigenetic alterations, including DNA methylation and histone modifications, play a pertinent role in the response to several anticancer treatments, including DNA damaging agents like Top I inhibitors.Although camptothecin derivatives are used clinically as Top I inhibitors for management of cancer, certain types of cancer have inherent and or acquired resistance that limit the curative potential of them.Epigenetic modifications like DNA hypomethylation can either increase or decrease sensitivity to Top I inhibitors by different mechanisms.The combination of Top I inhibitors with the inhibitors of histone modifying enzymes can result in enhanced cytotoxic effects and sensitization of resistant cells to Top I inhibitors.MicroRNAs were found to directly influence the expression of Top I and other proteins in cancer cells resulting in positive or negative alteration of the response to Top I inhibitors.lncRNAs and their genetic polymorphisms have been found to be associated with Top I function and the response to its inhibitors.Clinical trials of epigenetic drugs in combination with Top I inhibitors are plentiful and some of them showed potentially promising outcomes.

Keywords: Cancer; DNA methylation; Top I; Top I inhibitors; epigenetic; histone modifications; noncoding RNAs; resistance.

Figure 1.

Resistance mechanisms to Top I inhibitors in cancer. (a) Overexpression of efflux transporters (PgP, ABCB1, MRP, ABCC and BCRP) can reduce the cellular abundance of Top I inhibitors. (b–e) Mutations in Top I gene, reduced Top I expression and phosphorylation levels and reduced sumoylation of Top I enzyme itself can decrease the affinity of Top I inhibitors to their target. (f) Overexpression of tyrosyl-DNA phosphodiesterase 1 (TDP-1) can increase the rate of cleavage of the covalent linkage between stabilized Top1 with DNA and reverses the formation of cleavage complex. All these events lead to the development of resistance to Top I inhibitors. PgP: P-glycoprotein; ABCB1: ATP Binding Cassette Subfamily B Member 1; MRP/ABCC: multidrug resistance related protein; BCRP/ABCG2: breast cancer resistance protein; Top I: topoisomerase I; TDP-1: tyrosyl-DNA phosphodiesterase 1.

Figure 2.

Effect of DNA hypomethylation on the response of cancer cells to CPTs. (A) mechanisms by which hypomethylation can increase sensitivity to CPTs including: decreased expression of Bcl-2 anti-apoptotic protein, increased number of replication forks in early S phase, demethylation of the Top I promoter or indirect stimulation of Top I expression and restored expression of DEXI protein. (B) Mechanisms by which hypomethylation can decrease sensitivity to CPTs including protection of newly synthesized DNA from cleavage complex stabilization and DNA fragmentation, elevated expression of UGT1A1 metabolizing enzyme which is responsible for irinotecan’s inactivation and elevated expression of WRN helicase enzyme.

Figure 3.

Effect of targeting histone modifying enzymes on cellular response to CPTs. Gene deletion or inhibition of HATs, inhibition of histone deacetylation by HDACi or inhibiting BET, KDMs and EZH2 result in higher DNA damage levels, ROS generation, increase in caspase 3/7 activity and apoptosis induction. KDMi: histone lysine demethylase inhibitor; EZH2i: histone-lysine N-methyltransferase enzyme enhancer of zeste homolog 2 inhibitor; CPTs: camptothecins; Top I: topoisomerase I; HATi: histone acetyltransferase inhibitor; HDACi: histone deacetylase inhibitor; BETi: bromodomain and extraterminal domain inhibitor; DSBs: double strand breaks; ROS: reactive oxygen species.

Figure 4.

The involvement of miRNAs and lncRNAs in the response to Top I inhibitors. (A) miR-23a and miR-139 inhibit Top I expression. Thus, curbing their expression will in turn augment the enzyme’s expression. (B) Higher levels of miR-519c can lead to decreased ABCG2 expression leading to higher sensitivity to CPTs. (C) lncRNAs participate in maintaining genomic stability, cell survival and higher resistance to CPTs. Absence of lncRNAs can lead to persisitence of Top I cleavage complexes, increased chromosomal defects and better response to CPTs.