Transcriptional Selectivity of Epigenetic Therapy in Cancer

Abstract

A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation and ChIP-seq analyses the epigenetic response of a set of colon, breast and leukemia cancer cell lines to small molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343). We also characterized the effects of DAC as combined with the other compounds. Averaged over the cancer cell models employed, we found that DAC affected 8.6% of the transcriptome and that 95.4% of the genes affected were upregulated. DAC preferentially regulated genes that were silenced in cancer and that were methylated at their promoters. In contrast, Depsi affected the expression of 30.4% of the transcriptome but showed little selectivity for gene upregulation or silenced genes. S2101, UNC0638, and GSK343 affected only 2% of the transcriptome, with UNC0638 and GSK343 preferentially targeting genes marked with H3K9me2 or H3K27me3, respectively. When combined with histone methylase inhibitors, the extent of gene upregulation by DAC was extended while still maintaining selectivity for DNA methylated genes and silenced genes. However, the genes upregulated by combination treatment exhibited limited overlap, indicating the possibility of targeting distinct sets of genes based on different epigenetic therapy combinations. Overall, our results demonstrated that DNA methyltransferase inhibitors preferentially target cancer-relevant genes and can be combined with inhibitors targeting histone methylation for synergistic effects while still maintaining selectivity.

Panobinostat sensitizes KRAS‐mutant non‐small‐cell lung cancer to gefitinib by targeting TAZ

“…Although it is still not fully understood genome-wide regulation by panobinostat since HDAC inhibitors have a huge influence on transcriptome. 34 Our microarray data showed that combination therapy significantly downregulated YAP/ TAZ and EGFR signatures, and because we identified that TAZ and TAZ-mediated EGFR signaling was suppressed by panobinostat but not by gefitinib. Moreover, gefitinib has less response towards EGFR-wild-type/KRAS mutant NSCLC.…”

“…Additionally, panobinostat induced acetylation of histone and tubulin, suggesting that inhibition of HDAC by panobinostat may disrupt TAZ transcription and that attenuation of the chromatin structure by panobinostat may result in induction of tumor apoptosis. Although it is still not fully understood genome‐wide regulation by panobinostat since HDAC inhibitors have a huge influence on transcriptome . Our microarray data showed that combination therapy significantly downregulated YAP/TAZ and EGFR signatures, and because we identified that TAZ and TAZ‐mediated EGFR signaling was suppressed by panobinostat but not by gefitinib.…”

A dichotomy in association of core transcription factors and gene regulation during the activated B-cell to plasmablast transition

“…68 A feature of inhibition of epigenetic repressors including G9A has been evidence that acute loss of function leads to selective impact on target gene regulation without globally impairing epigenetic programs. 69, 70 G9A inhibition did not prevent the execution of the majority of the plasmablast program but led to a focused impact on gene expression consistent with a partial delay in differentiation. This included the gradual de-repression of genes which belonged predominantly within modules linked to BLIMP1 occupancy and silent epigenetic state.…”

Epigenetics and Precision Oncology

“…For example, in acute promyelocytic leukemia, the primary defect causing cancer is known to be a block in hematopoietic differentiation, which in the HL-60 cell line appeared to be most strongly affected by the combination of decitabine and the KDM1A inhibitor, S2101. In contrast, the greatest effect on re-expression of silenced tumor suppressor genes was seen in a colon cancer cell line, YB5, with the combination of decitabine and the EZH2 inhibitor GSK343 (71). These data suggest that specific combinations of targeted agents could be used to address the primary defects present in specific cancers.…”

“…In addition, combination regimens of cytotoxic chemotherapy and DNA methylation inhibitors have been shown to cause cell death in multiple in vitro settings, via a distinct calcium-dependent mechanism (70). Finally, recent in vitro data has highlighted the epigenetic specificity of different combinations of therapies in different cancer types (71). For example, in acute promyelocytic leukemia, the primary defect causing cancer is known to be a block in hematopoietic differentiation, which in the HL-60 cell line appeared to be most strongly affected by the combination of decitabine and the KDM1A inhibitor, S2101.…”