Deacetylase Plus Bromodomain Inhibition Downregulates ERCC2 and Suppresses the Growth of Metastatic Colon Cancer Cells

SIMPLE SUMMARY: In cancer cells, the DNA repair response can be exploited as an ‘Achilles heel’ to trigger programmed cell death pathways and tumor elimination. Rather than involving ‘naked’ DNA, repair occurs in the context of histone and non-histone proteins in the vicinity of the damage. Drugs that target different epigenetic mechanisms can lead to the synergistic downregulation of critical DNA repair factors, including those associated with poor survival in colorectal cancer patients. Notably, normal colonic epithelial cells are more resistant than colon cancer cells to the epigenetic drug combinations. In the current investigation, cell-based assays and preclinical animal models reaffirmed the crosstalk between DNA repair and epigenetic regulatory mechanisms, and provided new avenues for precision oncology and cancer interception. ABSTRACT: There is growing evidence that DNA repair factors have clinical value for cancer treatment. Nucleotide excision repair (NER) proteins, including excision repair cross-complementation group 2 (ERCC2), play a critical role in maintaining genome integrity. Here, we examined ERCC2 expression following epigenetic combination drug treatment. Attention was drawn to ERCC2 for three reasons. First, from online databases, colorectal cancer (CRC) patients exhibited significantly reduced survival when ERCC2 was overexpressed in colon tumors. Second, ERCC2 was the most highly downregulated RNA transcript in human colon cancer cells, plus Ercc2 in rat tumors, after treatment with the histone deacetylase 3 (HDAC3) inhibitor sulforaphane (SFN) plus JQ1, which is an inhibitor of the bromodomain and extraterminal domain (BET) family. Third, as reported here, RNA-sequencing of polyposis in rat colon (Pirc) polyps following treatment of rats with JQ1 plus 6-methylsulfinylhexyl isothiocyanate (6-SFN) identified Ercc2 as the most highly downregulated gene. The current work also defined promising second-generation epigenetic drug combinations with enhanced synergy and efficacy, especially in metastasis-lineage colon cancer cells cultured as 3D spheroids and xenografts. This investigation adds to the growing interest in combination approaches that target epigenetic ‘readers’, ‘writers’, and ‘erasers’ that are deregulated in cancer and other pathologies, providing new avenues for precision oncology and cancer interception.