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Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription

Oncogene volume 27, pages 6044–6055 (2008)Cite this article

Abstract

Mutated in colorectal cancer (MCC) was originally identified as a candidate gene for familial adenomatous polyposis (FAP) but further study identified adenomatous polyposis coli (APC) as responsible for FAP and the physiologic/pathologic roles of MCC remained poorly understood. Recently, MCC promoter methylation was discovered as a frequent early event in a distinct subset of precursor lesions and colorectal cancer (CRC) associated with the serrated CRC pathway. Here we provide the first evidence of the biological significance of MCC loss in CRC and the molecular pathways involved. We show MCC expression is dramatically decreased in many CRC cell lines and the distinct subset of sporadic CRC characterized by the CpG island methylator phenotype and BRAFV600E mutation due to promoter methylation as reported previously. Importantly, we find MCC interacts with β-catenin and that reexpression of MCC in CRC cells specifically inhibits Wnt signaling, β-catenin/T-cell factor/lymphoid-enhancer factor-dependent transcription and cellular proliferation even in the presence of oncogenic mutant APC. We also show that MCC is localized in the nucleus and identify two functional nuclear localization signals. Taken together, MCC is a nuclear, β-catenin-interacting protein that can act as a potential tumor suppressor in the serrated CRC pathway by inhibiting Wnt/β-catenin signal transduction.

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Acknowledgements

We thank Dr Kenneth W Kinzler, Dr Kazuo Maruyama, Dr Inder Verma, Dr Bert Vogelstein and Dr Bryan Williams for the various reagents used for this work as well as Lisa Krumroy and Alona Merkulova for technical assistance. This work was supported by grants to NS from the Cleveland Clinic Taussig Cancer Center/Scott Hamilton CARES Initiative and the National Cancer Institute Grant CA 100748.

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Author notes

  1. R Fukuyama

    Present address: 5Current address: Aichi Cancer Center, Nagoya 464-8682, Japan.,

  2. K P Ng

    Present address: 6Current address: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.,

Authors and Affiliations

  1. Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA

    R Fukuyama, R Niculaita, K P Ng, P P Aung, G Casey & N Sizemore

  2. School of Biomedical Sciences, Kent State University, Kent, OH, USA

    R Niculaita & N Sizemore

  3. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

    E Obusez, G Casey & N Sizemore

  4. Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA

    J Sanchez, M Kalady, G Casey & N Sizemore

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Correspondence to N Sizemore.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Fukuyama, R., Niculaita, R., Ng, K. et al. Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription. Oncogene 27, 6044–6055 (2008). https://doi.org/10.1038/onc.2008.204

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