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

Zeenat Jahan; Fahad A Benthani; Nicola Currey; Hannah W Parker; Jane E Dahlstrom; C Elizabeth Caldon; Maija R J Kohonen-Corish

doi:10.3390/cancers14122859

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

Cancers (Basel). 2022 Jun 9;14(12):2859. doi: 10.3390/cancers14122859.

Authors

Zeenat Jahan^{1

2}, Fahad A Benthani^{2

3}, Nicola Currey², Hannah W Parker^{1

4}, Jane E Dahlstrom⁵, C Elizabeth Caldon^{2

3}, Maija R J Kohonen-Corish^{1

2

4

6

7}

Affiliations

¹ Woolcock Institute of Medical Research, 431 Glebe Point Road, Glebe, Sydney, NSW 2037, Australia.
² Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
³ St. Vincent's Clinical School, UNSW Sydney, Sydney, NSW 2010, Australia.
⁴ Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia.
⁵ ACT Pathology, The Canberra Hospital and Australian National University Medical School, Canberra, ACT 2605, Australia.
⁶ Microbiome Research Centre, School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2217, Australia.
⁷ School of Medicine, Western Sydney University, Sydney, NSW 2560, Australia.

Abstract

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.

Keywords: CIMP; colorectal cancer; epigenetic biomarker; mutated in colorectal cancer (MCC); precision medicine.

Abstract

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