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

'MCC' protein interacts with E-cadherin and β-catenin strengthening cell-cell adhesion of HCT116 colon cancer cells.

E-cadherin and β-catenin are key proteins that are essential in the formation of the epithelial cell layer in the colon but their regulatory pathways that are disrupted in cancer metastasis are not completely understood. Mutated in colorectal cancer (MCC) is a tumour suppressor gene that is silenced by promoter methylation in colorectal cancer and particularly in patients with increased lymph node metastasis. Here, we show that MCC methylation is found in 45% of colon and 24% of rectal cancers and is associated with proximal colon, poorly differentiated, circumferential and mucinous tumours as well as increasing T stage and larger tumour size. Knockdown of MCC in HCT116 colon cancer cells caused a reduction in E-cadherin protein level, which is a hallmark of epithelial-mesenchymal transition in cancer, and consequently diminished the E-cadherin/β-catenin complex. MCC knockdown disrupted cell-cell adhesive strength and integrity in the dispase and transepithelial electrical resistance assays, enhanced hepatocyte growth factor-induced cell scatter and increased tumour cell invasiveness in an organotypic assay. The Src/Abl inhibitor dasatinib, a candidate anti-invasive drug, abrogated the invasive properties induced by MCC deficiency. Mechanistically, we establish that MCC interacts with the E-cadherin/β-catenin complex. These data provide a significant advance in the current understanding of cell-cell adhesion in colon cancer cells