MCC Gene Silencing Is a CpG Island Methylator Phenotype-Associated Factor That Predisposes Colon Cancer Cells to Irinotecan and Olaparib

Abstract

Simple SummaryDNA hypermethylation of specific regulatory regions causes gene silencing that is an important cancer-promoting mechanism. A subset of colorectal cancers display concordant hypermethylation and silencing of multiple genes, and this appears to change the way in which tumors respond to some cancer therapies. The aim of this study was to evaluate how the presence of the MCC gene silencing relates to the highly methylated subset of colorectal cancers and how it may affect therapy responsiveness. We found that strong MCC silencing is found throughout the hypermethylated subset, but MCC expression is also lost or reduced in some other tumors which show hypomethylated regions of the gene. In cell culture experiments, the deletion of MCC increased the responsiveness of cancer cells to the chemotherapy drug irinotecan (SN38), and this was further augmented by a targeted cancer drug, the PARP-inhibitor Olaparib.Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are potentially more responsive to the topoisomerase-inhibitor irinotecan. The mechanistic basis of the increased sensitivity of CIMP cancers to irinotecan is poorly understood. Mutated in Colorectal Cancer (MCC) is emerging as a multifunctional tumor suppressor gene in colorectal and liver cancers, and has been implicated in drug responsiveness. Here, we found that CIMP tumors undergo MCC loss almost exclusively via promoter hypermethylation rather than copy number variation or mutations. A subset of cancers display hypomethylation which is also associated with low MCC expression, particularly in rectal cancer, where CIMP is rare. MCC knockdown or deletion was found to sensitize cells to SN38 (the active metabolite of irinotecan) or the PARP-inhibitor Olaparib. A synergistic effect on cell death was evident when these drugs were used concurrently. The improved SN38/irinotecan efficacy was accompanied by the down-regulation of DNA repair genes. Thus, differential methylation of MCC is potentially a valuable biomarker to identify colorectal cancers suitable for irinotecan therapy, possibly in combination with PARP inhibitors.